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Autophagy and cancer

Autophagy and cancer

Article Canceer PubMed Google Scholar Nagy P, et al. O'Toole ; Patrick S. Autophagy and cancer, sustained Auhophagy of growth factors induces apoptosis with Autophagy and cancer of caspases cabcer cleave Beclin-1, Detoxification Programs for Addiction distinct Autophagy and cancer. Here, Autophagy and cancer proteins of the ATG8 Autophagy and cancer ATG8 in yeast; LC3A, B, C, GABARAPs, and GATE proteins in mammals are post-translationally modified by lipidation, first by exposure of a C-terminal glycine and subsequent conjugation to phosphatidylethanolamine PE. Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells. Anyone you share the following link with will be able to read this content:. The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner.

Autophagy and cancer -

Cancer cells display activation of distinct mechanisms for adaptation and growth even in the presence of stress. Autophagy is a catabolic mechanism that aides in the degradation of damaged intracellular material and metabolite recycling.

This activity helps meet metabolic needs during nutrient deprivation, genotoxic stress, growth factor withdrawal and hypoxia. However, autophagy plays a paradoxical role in tumorigenesis, depending on the stage of tumor development. Early in tumorigenesis, autophagy is a tumor suppressor via degradation of potentially oncogenic molecules.

However, in advanced stages, autophagy promotes the survival of tumor cells by ameliorating stress in the microenvironment.

These roles of autophagy are intricate due to their interconnection with other distinct cellular pathways. In this review, we present a broad view of the participation of autophagy in distinct phases of tumor development.

Moreover, autophagy participation in important cellular processes such as cell death, metabolic reprogramming, metastasis, immune evasion and treatment resistance that all contribute to tumor development, is reviewed.

Finally, the contribution of the hypoxic and nutrient deficient tumor microenvironment in regulation of autophagy and these hallmarks for the development of more aggressive tumors is discussed. Eukaryotic cells, over their lifespan, are continuously exposed to a variety of physical, chemical, and biological stresses that result in homeostatic imbalance.

However, cells are equipped with a set of intracellular defense mechanisms to neutralize and adapt to such stress. Macroautophagy, hereafter referred to as autophagy, is an adaptation mechanism to preserve cellular integrity and viability.

Intracellular content, including proteins, organelles and portions of cytoplasm, are sequestered in double-membrane structures, called auto phagosomes, that are delivered to lysosomes for degradation of their content 1.

Autophagy is strictly regulated by a variety of genes termed autophagy-related genes ATG. Autophagy in the absence of stress is active at basal levels to degrade damaged cellular components and recycle nutrients to preserve the energetic state of the cell 2.

However, in response to stresses, such as nutrient deprivation, hypoxia, genotoxic stress, accumulation of misfolded proteins, inhibition of protein synthesis or presence of pathogens, autophagy is upregulated to maintain cellular homeostasis 1. Autophagy is dysregulated in distinct pathological conditions, such as infection, aging, neurological disorders and cancer.

Autophagy in cancer cells is considered a double-edged sword since, in initial stages of tumorigenesis, it may act as a tumor suppressor by degrading potentially harmful agents or damaged organelles, thus avoiding the spread of damage including DNA alterations 3. However, in advanced stages of tumor development, autophagy is a tumor-promoting mechanism because of its ability to sustain tumor viability in stressful microenvironments.

Besides this tumor-promoting activity, autophagy makes a notable contribution to resistance to distinct types of therapy, representing a serious obstacle for successful treatment 4. According to Hanahan and Weinberg, tumor cells exhibit eight particular characteristics, called as hallmarks of cancer, that include sustained proliferation, evasion of growth suppressing signals, replicative immortality, angiogenesis, immune escape, evasion of cell death, metabolic reprogramming and activation of invasion and metastasis 5.

Recent reports demonstrate that autophagy is associated with some of these hallmarks. For example, autophagy and apoptosis are typically considered as opposite pathways, yet under specific biological circumstances, they act in a cooperative fashion for cell demise.

Little is known concerning crosstalk between these pathways in the early stages of cancer development, but an increasing body of evidence suggests that under stressful conditions associated with cancer, autophagy and apoptosis cooperate to limit the growth of incipient tumor cells.

Kitanaka et al. reported that autophagy participates in spontaneous regression of high expressing-RAS neuroblastoma.

Dying cells during regression do not exhibit morphological and biochemical signs of apoptosis, suggesting that autophagy may serve as an additional mechanism for cell death 6. Nutrient demand is increased as tumors develop to sustain cell proliferation.

Moreover, the uncontrolled proliferation of cells leads to critical fluctuations in the availability of nutrients. Tumor cells display reprogrammed metabolism adapted to stress induced by decreased supplies of essential nutrients.

Additionally, some metabolites derived from metabolic reprogramming, activate autophagy to increase recycling of nutrients and sustain tumor viability. Autophagy thus provides tumor cells with metabolic plasticity to tumor cells due to the diversity of substrates degraded 7.

The role of autophagy in epithelial to mesenchymal transition as well as during metastasis will also be discussed. Autophagy participates in promoting cell survival against stressful conditions elicited along with these processes 8.

In this review, we will discuss the role of autophagy during tumor development, from early to late stages of tumor growth. Moreover, crosstalk between autophagy and apoptosis, metabolic reprogramming, and metastasis will be examined. Further, the emerging role of autophagy as an immune evasion mechanism is considered.

Finally, the repercussions of autophagy in resistance to distinct cancer treatments are assessed. The mammalian autophagic process can be divided in three phases: phagophore formation, elongation of isolation membranes, and maturation.

During starvation, intracellular levels of AMP increase leading to AMPK activation 9. The direct mechanism is due to AMPK-mediated phosphorylation of ULK-1 at serine residues , , and , resulting in ULK activation Mutational-directed loss of these residues in ULK-1 in human osteosarcoma U-2 OS cells and mouse embryonic fibroblast MEF inhibits autophagy.

This loss leads to accumulation of damaged mitochondria In this sense, AMPK downregulates mTOR by phosphorylation of the tuberous sclerosis complex 2 TSC2 , which is an mTOR inhibitor, or by phosphorylation of the regulatory associated protein of mTOR Raptor 11 , When ULK-1, located in the nascent phagophore, activates class III phosphatidylinositol 3-kinase PI3K VPS34, conversion of phosphatidylinositol to phosphatidylinositol 3-phosphate is promoted by the VPS34, Beclin-1, VPS15, Atg14, and p complex 13 , The activity of this PI3K complex is modulated in two ways: ultraviolet irradiation resistance-associated gene and BAX-interacting factor 1 Bif-1 favoring its activity.

Conversely, members of the Bcl-2 family, such as Bcl-2 and Bcl-XL, or the run domain Beclin-1 interacting cysteine-rich containing protein Rubicon , have a negative effect on the activity of the complex 1.

In the latter case, Bcl-2 proteins interact with the BH3-binding region of Beclin-1 that prevents their interaction with VPS34, thus inhibiting autophagy.

Transgenic mice with Beclin-1 gene mutations in its BH3-binding region show higher levels of basal autophagy in distinct tissues compared to wild type mice 15 See Figure 1 , left panel. Figure 1. Regulation of the mammalian autophagy. Additional systems activate red arrows or inhibit blue arrows the activity and assembly of the complex.

The elongation of the isolation membrane requires the participation of two ubiquitin-like conjugation systems. The formation of the AtgAtg5-Atg16 complex involves the activity of Atg7 and Atg The LC3 requires the participation of Atg4 to hydrolyze LC3 into LC3-I, Atg3 as well as Atg7 for conjugation of LC3-II to pohosphatidyletanolamine PE.

Phagophore closure is regulated by members of ESCRT, CHMP2A VPS4. In the late steps of maturation and fusion, Dynein participates in the mobilization of auto phagosomes.

The fusion of auto phagosomes with lysosomes is mediated by members of the SNARE family. Created by BioRender. The next step, the elongation of isolation membranes, is regulated by two ubiquitin-like conjugation systems: Atg5-Atg12 and LC3 pathways.

The Atg5-Atg12 complex is formed by Atg12 activation by Atg7 and transfer to Atg10 before conjugation with Atg5. Finally, the complex Atg5-Atg12 is non-covalently conjugated to Atg16 to form the complex Atg5-AtgAtg16 that displays E3 ligase activity Conversely, the LC3 pathway begins with the C-terminus cleavage of LC3 by the protease, Atg4B, to generate the soluble form, LC3-I.

LC3-I is then conjugated to phosphatidylethanolamine PE by Atg7, Atg3 and the Atg5-AtgAtg16 complex, producing the LC3-II conjugated form 1 See Figure 1 , mid-panel. Some proteins, such as p62 also known as sequestosome-1 , NBR1 and NIX harbor an LC3-interacting region LIR which facilitates the recognition of ubiquitylated proteins or specific organelle membranes to selectively deliver cargo to auto phagosomes 17 , Although Atg5 and Atg7 are crucial molecules for autophagy, recent studies show that autophagy can be induced by etoposide in Atg5 or Atg7-deficient MEF For phagophore closure in the canonical pathway, participation of members of the endosomal sorting complex required for transport ESCRT , mainly CHMP2A and the vacuolar protein sorting-associated-4 VPS4 , is required CHMP2A is translocated to the edge of phagophore structures in this process to promote closure of the membranes.

Also, VPS4 locates on the outer leaf of nascent autophagosomal membranes to promote disassembly of ESCRT molecules in an ATP-dependent manner 20 See Figure 1 , right panel. Experiments carried out in U-2 OS cells demonstrate that genetic inhibition of CHMP2A or VPS4 impairs phagophore closure, preventing the formation of nascent auto phagosomes and causing late fusion with lysosomes Finally, in the maturation step of auto phagosomes, LC3-II located in the outer autophagosomal membrane is delipidated, and auto phagosomes fuse with lysosomes to form auto phagolysosomes, leading to degradation of auto phagosome content by several hydrolytic enzymes 1.

Auto phagosome-lysosome fusion is mainly regulated by soluble NSF attachment protein receptors SNAREs , specifically Qa-SNARE, syntaxin 17, Qbc-SNARE and lysosomal R-SNARE Also, small GTPase Rab7 and the homotypic fusion and protein sorting participate in auto phagolysosome formation 22 See Figure 1 , right panel.

Autophagy and apoptosis represent two self-regulatory mechanisms by which cells respond to different types of stresses and death stimuli to maintain homeostasis.

Apoptosis is a type of regulated cell death related to the elimination of cells and tissues during embryonic development and also in the removal of damaged cells in adult organisms, thus limiting their proliferation Apoptosis is classified in two mechanisms depending on the type and the source of stress.

The intrinsic pathway of apoptosis is activated by intracellular stressors such as DNA damage, endoplasmic reticulum stress, accumulation of reactive oxygen species ROS , and mitotic defects In contrast, the extrinsic pathway is triggered by extracellular stress and is sensed by distinct death receptors expressed on cell surfaces.

Such factors include tumor necrosis factor receptor 1A TNFR1A and Fas cell surface receptor FAS. Activation of extrinsic pathway requires the formation of the death-inducing signaling complex which in turn requires association with TNFRSF1A associated via death domain TRADD and Fas-associated via dead domain FADD to TNFR or FAS, respectively Both pathways converge in the induction of permeability in the mitochondrial outer membrane, releasing a wide variety of apoptogenic molecules leading to cellular disassembly.

Although autophagy and apoptosis act antagonistically, under specific biological conditions, their crosstalk can lead to cooperation for cellular demise. Currently, accurate molecular interactions of apoptosis-autophagy crosstalk in cancer remain unclear.

In the present section, we discuss the participation of key regulatory molecules shared between processes and their impact on cancer, focusing on early stages of tumor development.

As previously mentioned, Beclin-1 is an important protein in the early stages of autophagy. Several studies demonstrate that autophagy may serve as a tumor suppressor. These findings suggest that Beclin-1 is important for the development of cancer and may serve as a tumor suppressor.

Loss of Beclin-1 blocks activation of autophagy, and thus precludes its cytoprotective role. This impairment of degradation of potentially carcinogenic agents or damaged organelles leads to the spreading of damage inside cells and increases the risk of cancer development.

Monoallelic loss of beclin-1 gene in a mouse model of breast cancer led to increased signs of DNA damage and activity of repair systems, therefore increasing the chance for introduction of mutation and thus the risk of tumorigenesis Besides autophagy, Beclin-1 is implicated in apoptotic cell death, representing a node of crosstalk between these mechanisms In vitro experiments show that Beclin-1 overexpression in gastric cancer and glioblastoma cell lines induces apoptosis upon exposure to cytotoxic agents 29 , These pro-apoptotic properties of Beclin-1 might be explained by two mechanisms.

First, as Beclin-1 interacts through its BH3-only domain with Bcl-2 anti-apoptotic molecules, Beclin-1 overexpression may release pro-apoptotic molecules such as BAX and BAK from Bcl-2 to promote intrinsic apoptosis Figure 2 , right panel.

Additionally, caspase-mediated cleavage of Beclin-1 promotes apoptosis. However, sustained depletion of growth factors induces apoptosis with activation of caspases which cleave Beclin-1, rendering distinct fragments.

It is possible that in early stages of carcinogenesis, loss of Beclin-1 affects autophagy induction, and also impacts apoptosis regulation, especially in cells with molecular alterations in apoptotic genes.

Figure 2. Crosstalk of autophagy and apoptosis in cancer. Potential carcinogenic agents induce distinct types of stress in cell, triggering autophagy or apoptosis. Under certain threshold of damage, stress-responsive transcription factors such as p53 or FOXO promote the upregulation of genes involved in control and activation of autophagy, thereby neutralizing the damage.

However, if the carcinogenic stimulus persists and damage is above threshold, autophagic proteins interact with pro- or anti- apoptotic molecules triggering intrinsic or extrinsic apoptosis, therefore limiting the growth of incipient tumor cells. Members of the Atg5-AtgAtg16 complex are also involved in the interplay between autophagy and apoptosis.

This complex, as previously mentioned, is part of an ubiquitin-like conjugation system active in the elongation phase of autophagy. Specifically, some findings relate Atg12 protein to apoptotic cell death.

Atg12 harbors a BH3-like domain within its structure and physically interacts with anti-apoptotic Bcl-2 molecules such as Mcl-1 and Bcl-2 This interaction may release pro-apoptotic molecules to induce intrinsic apoptosis.

For example, Atg12 expression is regulated by distinct transcription factors, such as factors in the forkhead homebox transcription factor family FOXO that are induced by different stressors Atg12 is overexpressed after different carcinogenic insults, suggesting that it might participate in autophagy and apoptosis induction in the early stages of carcinogenesis In , Yoo et al.

transfected rat intestinal epithelial cells with oncogenic H-RAS and observed that Atg12 was downregulated in these cells due to increased proteasomal degradation, mediated by MAPK activation.

In addition, this same group demonstrated that ectopic expression of Atg12 in oncogenic-RAS intestinal epithelial cells resulted in decreased clonogenicity and increased cell death by apoptosis Although increased expression of Atg12 has been found in certain solid tumors, in the early stages of carcinogenesis it might participate in the induction of autophagy also in activation of apoptosis.

In vitro studies using HeLa cells indicate that IFN-γ treated cells die by apoptosis preceded by autophagy. Cell death is dependent on expression and interaction of Atg5 and FADD 36 Figure 2 , right panel. Although precise molecular mechanisms remain elusive; the extrinsic pathway of apoptosis is presumably activated.

We propose a similar phenomenon in the early stages of carcinogenesis, especially considering the participation of immune response.

Immunoediting theory suggests that, during the elimination phase, immune cells remove incipient tumor cells through different mechanisms, involving the release of some cytokines such as IFN-γ Accumulation of this cytokine could lead to the elimination of nascent tumor cells. Moreover, similar to Beclin-1, Atg5 is cleaved by calpain rendering fragments that localize in the mitochondria and promote the release of pro-apoptotic molecules Another important molecule participating in the crosstalk between autophagy and apoptosis is the BH3-only protein, BIM.

BIM interacts with other pro-apoptotic members of the Bcl-2 family during apoptosis to induce the release of apoptogenic molecules from mitochondria, thereby activating the intrinsic pathway BIM is present in cells in three splice variants: BIM-short BIM S , BIM-long BIM L , and BIM-extra-long BIM EL BIM S and BIM EL participate in apoptosis induction, BIM L displays an important role in autophagy.

In IL-7 cultured T-lymphocytes, BIM L localizes in mature lysosomes through interaction with dynein BIM L silencing was not reported, however, lack of BIM L may affect fusion of lysosomes with phagosomes and subsequent degradation of contents.

BIM polymorphisms are detected in lung cancer patients We propose that participation of BIM in cancer is crucial since its loss in early stages of carcinogenesis impairs both apoptosis and autophagy, leading to the emergence of tumors.

Another key modulator of autophagy and apoptosis is the tumor suppressor protein TP53, hereafter referred to as p p53 is an intracellular sensor of stress caused by genotoxic agents or activation of oncogenes Under non-stressed conditions, p53 is degraded in the cytoplasm by the E3-ubiquitin ligase MDM2.

However, different cellular insults cause stabilization of this protein and localization in the nucleus. In turn, p53 presence in the nucleus leads to upregulation of transcription of distinct genes involved in cell cycle control, repair of damaged DNA, apoptosis and autophagy p53, activated by genotoxic stress, induces autophagy by upregulation of AMPK, thus increasing expression of its β-1 and β-2 subunits and TSC-2, leading to mTOR inhibition, as discussed above In addition, animal models show that the absence of Atg7 induces pancreatic neoplasia without progression to an aggressive phenotype in mice expressing mutated K-RAS.

However, the concomitant loss of p53 leads to development of more aggressive pancreatic tumors. Further, p53 activated cell cycle arrest and apoptosis during early stages of tumor development in defective autophagy cells, limits tumor growth These findings suggest that autophagy protects cells from the damage induced by oncogenic signals.

Additionally, whether autophagy is defective, p53 limits tumor development by arresting or eliminating incipient tumor cells. Nuclear p53 also regulates the transcription of the damage-regulated autophagy modulator DRAM that represents another point of crosstalk between autophagy and apoptosis.

In A lung cancer cell lines, soon after exposure to mitochondrial inhibitors or genotoxic agents, DRAM was localized in lysosomes, regulating the process of autophagy in a pdependent manner Specifically, DRAM participates in LC3-I to LC3-II conversion, lysosomal acidification, and degradation 46 Figure 2 , right panel.

However, sustained stress promotes participation of DRAM in apoptosis, a phenomenon again dependent on p Once cathepsin-B is in cytosol, cleaves Bid into t-Bid provoking the release of apoptogenic molecules from mitochondria 47 Figure 2 , right panel.

In ovarian cancer, DRAM is downregulated in cell lines and tumor samples of advanced stages, highlighting its participation as a tumor suppressor gene Evidence is poor for participation of DRAM in cancer onset, and we propose that is important in autophagy-dependent clearance of damaged organelles elicited by potentially carcinogenic stimuli sensed by p53, hence, preserving cellular viability.

Nonetheless, if carcinogenic stimuli persist or damage is above certain threshold, DRAM might participate in the induction of apoptosis of incipient cancer cells.

Thus, according to the experimental findings and propositions, during early stages of tumor development autophagy and apoptosis cooperate to prevent damage elicited by carcinogenic stimuli or eliminate damaged cells.

However, more experimental evidence is required to demonstrate the precise molecular mechanisms governing the crosstalk between these processes during tumor development.

Notably, crosstalk between autophagy and apoptosis in cancer is not steady during tumor progression. Instead, it is modified by intracellular and extracellular perturbations affecting both processes. As tumors evolve, extracellular perturbations caused by a limited influx of nutrients and oxygen modify uptake and metabolism of nutrients and production of intermediary metabolites.

Some of these metabolites regulate autophagy activation. Thus, autophagy can be activated via extracellular perturbations, inhibiting cell death, and sustaining cell viability. The ability of cells to adapt to stress requires diverse changes in cellular processes, including metabolic pathways.

Autophagy is a principal pathway for adaptive metabolic response, an important survival process. Tumor cells reorganize metabolic pathways to supply ATP, building blocks for macromolecule biosynthesis, and redox molecules required to cell proliferation, invasion, migration, and other processes essential for malignancy, including chemo resistance Consequently, the current research focus on metabolic reprogramming on the development and progression of human cancers reflects these hallmarks of cancer 5 , Otto Heinrich Warburg was the first author to identify changes in the metabolism of tumor cells; he demonstrated that cancer cells avidly consume glucose and excrete high amounts of lactate when oxygen is present.

He concluded that tumor cells increase glucose consumption and lactate production because of mitochondrial function This effect was termed the Warburg effect, or aerobic glycolysis In normal cells, mitochondria oxidize glucose in the presence of oxygen to obtain ATP via the tricarboxylic acid cycle TCA and electron transport chain.

The Warburg effect was initially considered a disadvantage for cancer cells, considering that the amount of ATP produced by the glycolytic pathway much less in comparison to mitochondrial ATP production Nevertheless, glycolysis is the fastest way that cells obtain ATP from the glucose breakdown, and occurs independently of oxygen.

Tumor growth is unorganized and the tumor microenvironment is poorly oxygenated; hence, glycolysis allows cancer cells to proliferate even in hypoxic conditions Additionally, this metabolic pathway provides building blocks necessary for other metabolic pathways, such as the synthesis of fatty acids, nucleotides and serine 55 , The Warburg effect is a metabolic adaptation associated with cell transformation that requires oncogene activation, such as RAS, AKT 57 , and MYC 58 , and the inhibition of tumor suppressors, such as p53 59 , MYC and RAS activation impair decarboxylation of pyruvate, leading to reduce acetyl-CoA production, an essential metabolite in TCA cycle Moreover, in RAS transformed cells, acetyl-CoA production is affected by inhibition of β-oxidation of fatty acids Further, uptake of glucose and glutamine in MYC transformed cells is enhanced along with glycolysis and glutaminolysis 1.

Autophagy supports broad metabolic plasticity to tumor cells, providing biomolecules to almost all carbon metabolic pathways, based on the diversity of substrates degraded 63 , For example, the breakdown of several carbohydrates into monosaccharides can fuel glycolysis, and proteins break down into amino acids or degradation of lipids in fatty acids provides substrates necessary for the TCA cycle.

This process is essential for metabolic reprogramming 64 , Autophagy in tumor cells is closely associated with oncogenic activators and tumor suppressors. Uncontrolled proliferation of malignant cells causes loss of tissue architecture. This structural tissue alteration promotes dysfunctional distribution of nutrients, growth factors, and oxygen within a tumor.

Deficient formation of vasculature in the tumor supports the development of heterogeneous tumor microenvironments that differ depending on tumor region 5. The concentration of oxygen is a crucial parameter affected by the heterogeneous nature of tumors.

These hypoxic conditions trigger cellular mechanisms to maintain homeostasis. Hypoxia-inducible factor 1 HIF-1 is a primary transcriptional regulator during hypoxic conditions. HIF-1 is a complex of two subunits, α and β.

The α subunit is degraded under normoxic conditions oxygen-rich 69 , However, during hypoxia ubiquitylation of the α subunit is decreased, promoting HIF-1 stability. HIF-1 binds to hypoxia-responsive element DNA sequences, facilitating a metabolic shift from oxidative phosphorylation OXPHOS to glycolysis In tumor cells, HIF-1 upregulates expression of over 80 genes that are critical in glucose metabolism, cell survival, tumor angiogenesis, invasion, and metastasis, independent of oxygen concentration However, glycolysis is strictly regulated.

The hexokinase HK family in mammalian cells catalyzes the conversion of glucose to glucose 6-phosphate G6P , representing the first rate-limiting step in glycolysis and other metabolic pathways such as pentose phosphate and gluconeogenesis Phosphofructokinase PFK is another regulatory enzyme essential in regulating glycolysis.

High levels of ATP allosterically inhibit the enzyme, decreasing affinity to fructose 6-phosphate. In addition, pH also regulates PFK activity.

Nonetheless, overexpression or specific mutations in cancer cells in HK proteins is associated with poor prognosis Specifically, mutations in the catalytic site of PFK enzyme are promoted in the oncogenic process.

In glioblastomas, AKT is degraded by polyubiquitylation leading to increased PFK activity, and consequent increase glycolysis, cell proliferation, and tumor growth Some tumor cells generally express high levels of isoform M2 pyruvate kinase PKM2 and low levels of isoform M1 of pyruvate kinase PKM1 , a specific regulatory enzyme of glycolysis.

Overexpression of PKM1 promotes glycolysis and inhibits mitochondrial oxidative phosphorylation. Use of stable isotope tracers e. Using this experimental strategy, it is possible to trace the fate of biosynthetic fuels through analysis of downstream isotope enrichment of labeled nutrients.

Experiments in cancer patients confirmed that i glucose is metabolized through glycolysis and the mitochondrial TCA cycle and ii a significant fraction of the acetyl-CoA used in the TCA cycle is not derived from blood-borne glucose 78 — This information casts doubt on the glycolysis dependency in tumor cells.

Besides, accumulating evidence suggests that mitochondrial metabolism is required in tumor cells and is crucial for tumorigenesis, treatment resistance, migration, and metastasis. Some tumors overexpress critical metabolic enzymes and pathways associated with the mitochondrial metabolism.

Progression in these tumors is driven by oncogenes and is associated with poor prognosis 52 , 74 , For example, several cancer mutations in TCA cycle-associated enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, contribute to mitochondrial dysfunction during tumorigenesis 82 , Autophagy in this case might be essential for providing substrates for anaplerotic reactions, such as amino acids through protein degradation or lipids through turnover, to sustain mitochondrial metabolism Most glucose is consumed by glycolysis, and glutamine becomes the primary substrate for the mitochondrial TCA cycle and generation of fatty acids and NADPH.

Autophagy supports necessary metabolic rearrangements which makes cells highly dependent on autophagy for survival. Metabolites, oxygen concentration, and oncogenes all regulate the initiation of auto phagosome formation, and regulation of autophagy is finely balanced by the integration of these signals.

Autophagy is strongly induced in response to nutrient starvation, primarily controlled by mTOR Glutamine is the most abundant free amino acid and becomes physiologically essential in conditions of high proliferation.

Glutaminolysis is the pathway that cells employ to transform glutamine to α-ketoglutarate, an irreversible reaction catalyzed by glutaminase GLS and glutamate dehydrogenase.

In cancer cells, increased consumption of glutamine has been linked to regulation of oncogenes like MYC. Overexpression of MYC correlates with expression of cellular transporter of glutamine, SLC1A5, and enhances glutamine consumption in cancer cells 84 , Glutaminolysis is proposed as an essential metabolic pathway in tumor cells that supplies carbon for anaplerotic pathways, such as TCA 86 , Proliferating cancer cells require high quantities of fatty acids and lipids to generate new membranes.

Citrate is diverted from the TCA cycle to sustain fatty acid synthesis, causing TCA cycle disruption, and compelling cancer cells to consume alternative nutrients to reestablish the TCA cycle 87 , Hence, glutamine stimulates the production of α-ketoglutarate, reconstituting the TCA cycle.

In addition, glutamate produced by GLS is necessary for the synthesis of glutathione GSH , an intracellular antioxidant that contributes to mitigation of oxidative stress in proliferating cells 88 , However, in cancer cells this link between mTORC1 and glutaminolysis acts in both directions.

Starvation leads to the activation of forkhead box O3 FOXO3 , which in turn, increases the expression of glutamate-ammonia ligase, the enzyme that resynthesizes glutamine from glutamate. The increase in glutamine synthesis abolishes the production of α-ketoglutarate from glutaminolysis, and thus inhibits mTORC1 and enhances autophagy 86 , α-ketoglutarate might activate mTORC1 and inhibit autophagy through an alternative mechanism involving acetyl-CoA synthesis and protein acetylation Further, despite the inhibitory effect of glutaminolysis on autophagy, a by-product of glutaminolysis, ammonium, has a dual role in autophagy, activating this process at low concentrations and inhibiting it at higher concentrations Reprogramming of glucose and amino acid metabolism is accompanied by alterations in lipid metabolism in tumor cells to meet energy demands for sustaining viability and proliferation Figure 3.

Figure 3. Metabolic stress and autophagy. During the oncogenic process, the proliferation rate and the microenvironmental conditions promote that the tumor cells reprogram their metabolism. Consequently, autophagy plays an essential role in this reprogramming, providing different substrates to feed the pathways of tumor cells.

However, the induction of autophagy depends on the stimuli to which the cell is subjected, the alteration of oncogenes such as MYC or RAS, the autophagy process is inhibited and during some microenvironmental tumor conditions such as hypoxia, autophagy is promoted.

Lipids represent a wide variety of molecules, including sterols, triacylglycerols, and phospholipids.

When energy supplies are plentiful, lipids are stored in cells as lipid droplets LD to avoid the accumulation of fatty acids in the cytosol However, starvation promotes degradation of lipids stored in LD into fatty acids that are then metabolized by β-oxidation to obtain large amounts of ATP.

Two primary metabolic pathways for lipid degradation within LD: neutral lipolysis and autophagic degradation. Neutral lipolysis involves the breakdown of lipids into fatty acids by cytosolic lipases which function under neutral pH environments In contrast, autophagic degradation of LD termed lipophagy involves sequestration of portions or entire LD into auto phagosomes with subsequent degradation in lysosomes by acidic lipases Lipophagy was firstly detected and studied in hepatocytes of starved mice More recently, the process was shown in starved adipocytes, neurons and immune cells 96 , The precise molecular mechanism of lipophagy is not clear.

It is initiated by recognition of LD mediated by p62, NBR1, and NDP52, which display LIR domains and interact with LC3-II present in phagophores The role of lipophagy in cancer is still unknown, since some studies report a positive effect in tumor progression and others a negative impact.

In , Lu et al. Further, fatty acid β-oxidation or autophagy inhibition, induced cell death after nutrient deprivation, suggesting that lipophagy protects tumor cells from starvation However, contrasting results were obtained in lung and hepatic tissue of knockout lysosomal acid lipase LAL mice that develop more tumors than wild type counterparts and display major susceptibility to metastasis.

Further, the absence of LAL was associated with increased release of tumor-promoting cytokines 99 , In this case, it seems that lipophagy could act as a tumor suppressor in the early stages of tumor development, and in advanced stages, in which environmental and metabolic alterations are present, lipophagy may promote tumor progression.

More studies are required to test this hypothesis. The metabolic implications of this process are profound and multifaceted. First, autophagy-mediated degradation and recycling of cell substrates supports metabolism and promotes survival and tumor growth.

Second, activation of autophagy in response to cancer therapy potentially leads to tumors resistance to conventional chemotherapy. Metastasis is a specific process of tumor aggressiveness, and most cancer patients die as a result of metastasis.

Metastasis is a response to the challenge of metabolic alterations and tumor microenvironment The unfavorable conditions in this microenvironment, such as hypoxia and lack of nutrients that occur during uncontrolled cell proliferation contribute to the development of metastasis Clear evidence exists of migration of tumor cells at early stages of tumor development, but the metastatic process is associated with advanced stages of tumors.

Autophagy plays an essential role in the metastasis cascade 8. The steps of this cascade are the invasion of tumor cells into the primary site, the intravasation, and survival of the tumor cells in blood or lymph, and finally, extravasation and colonization by tumor cells at a distant site.

Studies on the role of autophagy during the metastatic process are contradictory. Autophagy is reported to stop tumor cell metastasis , , but other authors suggest that autophagy favors metastasis , Molecules involved in autophagic process are upregulated during metastasis.

The LC3B protein is increased in lymph nodes of breast cancer patients compared to the primary tumor, and the expression of LC3B increases in advanced stages of disease LC3B also increases in metastases of melanoma and hepatocellular carcinoma compared to primary tumors Expression of autophagic molecules DRAM1 and p62 in glioblastoma correlates with a poor prognosis Other molecules with oncogenic activity, such as long non-coding RNA lncRNA MALAT1 in pancreatic cancer, increase autophagy during the metastatic process Blocking the expression of PD-L2 in osteosarcoma inhibits LC3-II and Beclin-1, impeding the ability of tumor cells to invade surrounding tissue As previously mentioned, hypoxia is an autophagic-inducing factor, but may also promote autophagy and cell migration.

IncRNA CPS1-IT1 in colorectal carcinoma suppresses expression of HIF-1α and decreases epithelium-mesenchymal transition EMT. Autophagy was observed in this study Levels of BNIP3, PI3KC3, and LC3-II were increased in a model of CoCl 2 -induced hypoxia in cholangiocarcinoma.

CoCl 2 at μM, accelerated cell migration due to upregulation of the metastasis marker, phosphorylated focal adhesion kinase pFAK Soluble factors in the tumor microenvironment, secreted in an autocrine or paracrine manner by the tumor cells, trigger metastasis, and autophagy One such factor is transforming growth factor TGF -β.

Exposure to TGF-β in non-small cell lung carcinoma cell lines, induced autophagy and EMT Autophagy and EMT are initiated in a TGF-β dependent manner in starved hepatocellular carcinoma cells The metastasis process begins with tumor cell invasion at the primary site and is coupled with EMT.

Neoplastic cells lose adhesion and contact with other cells because of the EMT program Loss of adhesion and activation of EMT trigger cell death stimuli that are avoided by activation of autophagy Autophagy is reported to be mainly involved in promoting cancer cell motility. Tumor cells must evade anoikis, a type of programmed cell death that occurs when a cell detaches from the extracellular matrix.

This process of cell death is mediated by apoptosis. Tumor cells can evade anoikis by activating autophagy Another mechanism involving autophagy during cell motility is the degradation of adhesion molecules, such as paxillin in auto phagosomes 8.

Interaction between cells and extracellular matrices ECM requires complex bonds called focal adhesions FA These junctions connect the cytoskeleton of epithelial cells with components of the ECM through integrins. On the extracellular side, integrins bind to ECM components, such as collagen, fibronectin, vitronectin, and laminin While in the interior of the cell, the integrins bind to the cytoskeleton by means of a protein complex formed by talin, vinculin, paxillin, zyxin, and α-actin , FA is regulated by the focal adhesion kinase FAK -Src, which is part of this complex.

FA bond composition varies among tissues and recognizes components of ECM, changes in the cell surface, and physiological and mechanical stress.

Dissociation of FA from ECM leads to cell death by apoptosis in a process called anoikis The disruption of integrins interactions with ECM activates FAK-Src, which suppresses survival signals such as ERK, PTEN, and NF-kB Lack of cell adhesion activates Bid and Bim, pro-apoptotic molecules that promote the assembly of BAX-BAK oligomers on the outer mitochondrial membrane, activating the intrinsic apoptosis pathway Death by anoikis might also occur via the extrinsic pathway since the loss of adhesion leads to downregulation of FLIP and increased expression of Fas and FasL The multi-functionality of FA allows detection of reduced integrin signaling that occurs after tumor cell detachment to the ECM.

The signal of cell detachment is translated as a signal of metabolic stress, activating pathways such as PI3K-AKT, which has a fundamental role in the regulation of integrins by growth factors such as epidermal growth factor and TGF-β.

These signals mediate a cellular survival response and inhibit pro-apoptotic proteins such as Bad, caspase-9, and glycogen synthase kinase 3b, among others , Tumor cells are remarkably resistant to anoikis, which favors cell motility and metastasis.

Autophagy is the primary mechanism of resistance to anoikis in cancer Fung et al. In hepatocellular carcinoma cells, cell detachment from the ECM produced inactivation of the mTORC1 complex and activation of autophagy, evading anoikis.

Also, astrocyte elevated gene 1 AEG-1 protein has a high correlation with metastasis in hepatocarcinoma. AEG-1 induces resistance to anoikis by activating autophagy Another molecule that induces resistance to anoikis by activating autophagy is miRa.

By inhibiting this miRNA, a decrease in Beclin-1 and Atg5 was observed, as well as an increase in cell death Figure 4.

Figure 4. Uncontrolled cell proliferation produces a high demand for oxygen and nutrients. As a result, the tumor becomes hypoxic and starved. These metabolic changes generate the activation of the epithelium-mesenchymal transition EMT program and the presence in the environment of factors that promotes metastasis and autophagy such as TGF-β.

Autophagy participates in two ways favoring cellular migration: a avoiding anoikis and b in the turnover of the focal adhesion. As previously mentioned, cell-ECM attachments are essential for cell homeostasis. During cell migration, FA is involved in generating tension and traction necessary for cell motility.

FA at the front of a cell is employed to anchor the cell to ECM, generating tension required to move the cell. At the rear of the cell, FA must be disassembled to producing advancing movement of the cell. This mechanical movement is termed FA turnover , , The metabolic stress produced by the lack of oxygen and nutrients in the tumor and the tumor microenvironment activates cellular motility.

Autophagy participates in FA turnover in this context, by degrading paxillin in auto phagosomes and disrupting FA. Sharifi et al. found that inhibiting autophagy suppresses metastasis to the lungs and liver without affecting tumor cell proliferation in a metastatic 4T1 mouse model of breast cancer 8 , Paxillin in breast cancer and melanoma metastasis serves as FA scaffolding and contains a LIR.

FAK-Src phosphorylates this domain in Y40, and paxillin is activated by LC3B and degraded via autophagy Paxillin is recruited via the c-Cbl cargo receptor and LC3 Finally, endothelial cells around the tumor secrete large amounts of the chemokine CCL5 that induces autophagy in tumor cells that display suppressed androgen receptors in a castration-resistant prostate cancer model.

These authors reported co-localization of paxillin in auto phagosomes in metastatic tumor cells, indicating that paxillin is degraded via autophagy, favoring the disassembly of FA and cell motility Figure 4.

The last step in the metastasis cascade is the colonization of host secondary organs. At this point, metastatic cells show EMT, detachment from ECM, intravasation and extravasation. Metastatic cells must reprogram their metabolism to cope with stress induced by metastasis processes.

Colonization represents a final challenging step for metastatic cells since target organs exhibit distinct environmental conditions from the primary tumor. Moreover, organs display varying environmental and metabolic conditions and exhibit distinct ECM composition, oxygen abundance and nutrient disposition When reaching host organs, metastatic cells encounter these distinct and hostile microenvironments.

Cells do not adapt to these adverse environmental conditions, may enter into a state of dormancy. These dormant cancer cells remain clinically undetectable and progress, causing tumor relapse, and organ failure. Signals responsible for triggering tumor outgrowth and colonization of secondary organs remain unknown, the participation of ECM components and aspects of tumor microenvironments likely play essential roles.

Dormant cells are characterized by a reversible growth arrest in G 0 -G 1 cell cycle phases, reduced metabolism and a stem-cell-like phenotype , To survive to this stage, dormant cells activate autophagy. Recent findings of Green et al. showed that autophagy inhibition in dormant breast cancer cells of mice decreased their viability, potential to growth and ability to form lung metastases in vitro and in vivo When metastatic cells are able to adapt to distinct environmental conditions, cells display a highly flexible metabolism that allows for colonization and formation of secondary tumor foci.

For example, metastatic cells attempting to invade and colonize lungs must adapt to the acute oxidative environment of these organs. To cope with oxidative toxicity, metastatic cells upregulate the expression of molecules controlling endogenous antioxidant responses, such as glutathione peroxidase 1, superoxide dismutase and peroxiredoxins , If these antioxidant defense mechanisms are not sufficient, oxidative damage is generated in organelles.

A growing body of evidence shows that accumulation of ROS triggers autophagy through distinct signaling pathways such as inhibition of PI3K-AKT-mTOR, and activation of AMPK and MAPK ROS-activated autophagy promotes degradation of damaged material or organelles In , Peng et al.

demonstrated in vivo that lung metastases of hepatocellular carcinoma cells exhibit higher levels of autophagy than primary tumors In addition, the same group demonstrated that genetic inhibition of autophagy of highly metastatic hepatocellular carcinoma cells blocked lung colonization potential without changing EMT activation, invasion and migration These findings do not provide information about the redox state of metastatic cells in intact and inhibited autophagy, but autophagy could, in theory, be important for protecting cells against oxidative damage in the lungs.

Another example is the colonization of the liver. The liver is characterized into zones with a varying oxygen gradient and high glucose concentrations, therefore showing hypoxic regions enriched with glucose. In this way, any metastatic cell seeking to establish in the liver must be able to adapt to hypoxic and glucose-rich conditions.

PDK-1 is a negative regulator of pyruvate dehydrogenase complex, thus reducing the entry of pyruvate to TCA cycle, decreasing mitochondrial activity, and promoting glycolytic metabolism.

Kim et al. reported that hypoxia-induced transcriptional upregulation of PDK-1 ensures the glycolytic synthesis of ATP, mitigation of hypoxic ROS production and inhibition of apoptosis Dupuy et al. reported that liver metastases upregulate their glycolytic activity under hypoxia by enhancing the activity of the PDK-1 PDK-1 also regulates autophagy in other cellular settings.

Quin et al. reported in acute myeloid leukemia cells that PDK-1 associates with ULK-1 promoting its activation and leading to induction of autophagy Mariño et al. reported, in starved human osteosarcoma cells and in mouse heart tissue, that genetic or pharmacological inhibition of PDK genes resulted in autophagy inhibition Participation of PDK-1 in autophagy induction during liver colonization by metastatic cells has not been studied, and we propose that besides promoting metabolic reprograming, PDK-1 also promotes autophagy as an adaptation mechanism to encourage the survival and colonization of liver by metastatic cells.

In the previous sections, we discussed the evolution of tumor microenvironments and how they sustain most hallmarks of cancer such as tumor growth, metabolic reprogramming, and cell death evasion, invasion and metastasis 5. In this sense, cellular components of the tumor microenvironment like endothelial cells, pericytes, cancer-associated fibroblasts and tumor-infiltrating immune cells play a key role in tumor growth 5.

The immune response is implicated as a key factor during tumor development. According to the cancer immunoediting theory, during early stages of tumor development, the immune system recognizes nascent tumor cells expressing neoantigens on major histocompatibility complex MHC molecules, thereby promoting tumor elimination mediated by natural killer NK cells or cytotoxic lymphocytes CTL However, immune-mediated elimination also represents a selective pressure, and highly immunogenic tumor cells are eliminated while less immunogenic tumor cells survive, avoiding immune recognition and destruction, a feature established as a hallmark of cancer 5 , Distinct immune evasion mechanisms have been reported.

For instance, decreased expression of death receptors; development of an immunosuppressive microenvironment through release of cytokines, such as TGF-β and IL, and recruitment of immunosuppressive cells Emerging evidence also demonstrates that autophagy plays a key role in protecting tumor cells against immune-mediated elimination.

In the present section, we discuss the participation of autophagy as an immune evasion strategy, focusing on NK and CTL-mediated elimination. Autophagy is induced in response to adverse conditions elicited by the tumor microenvironment, such as nutrient deprivation and hypoxia.

Tumor cells activate autophagy to help meet energy demands and sustain viability and proliferation. Additionally, in Noman et al. reported that hypoxic conditions impaired elimination of non-small cell lung carcinoma cells by autologous CTL They found that stabilization of HIF-1α and increased phosphorylation of the signal transducer and activator of transcription 3 pSTAT3 , in tumor cells, were associated with evasion of immune surveillance.

Further studies performed by this group demonstrate that hypoxia-induced autophagy is responsible for this phenomenon since pharmacologic or genetic inhibition of autophagy in hypoxic conditions restored susceptibility of tumor cells by CTL elimination Further, inhibition of autophagy during hypoxia promoted pSTAT3 degradation in proteasome in a pdependent manner.

Autophagy degrades p62 and consequently enhances the accumulation of pSTAT3. However, the mechanism by which hypoxia promotes the dissociation of pSTAT3 from p62 remains unclear. Molecular mechanisms are not completely studied, but STAT3 activation by hypoxia-induced autophagy in tumor cells could, in theory, help in escaping CTL-mediated elimination, since this transcription factor controls the expression of anti-apoptotic genes See Figure 5 , upper panel.

Figure 5. Autophagy as an immune evasion mechanism. Autophagy induced by environmental stress such as hypoxia promotes the escape to CTL or NK mediated elimination of tumors cells.

A Hypoxia, by an undefined mechanism, releases pSTAT3 from p62, thereby degrading p62 by autophagy and favoring pSTAT3 nuclear localization to up-regulate transcription of antiapoptotic genes. B During hypoxia, tumor cells activate autophagy to sequester and degrade cytotoxic granules released by NK cells or CTLs, thus impeding the elimination of tumor cells.

C Selective ER phagy might participate in degradation of MHC-l molecules during their biogenesis. NBR1 associate to MHC-l molecules or their chaperones in ER. Decreased surface expression of MHC-l molecules leads to impaired recognition by innate or adaptive immune cells, leading to escape for immune-mediated elimination.

Autophagy is also implicated in decreased susceptibility of tumor cells to elimination by NK cells. Baginska et al. reported, in MCF-7 breast cancer cells, that hypoxia-induced autophagy blocked NK cell-mediated lysis of tumor cells In this study, recognition of tumor cells by NK cells and NK cell degranulation were not affected by hypoxia.

Instead, tumor cells sequestered granzyme B and perforin granules inside auto phagosomes for subsequent degradation. Results obtained in this work led us to propose that a similar mechanism of cytoprotection elicited by autophagy could be responsible for impaired elimination of tumor cells by CTLs, such as granzyme B and perforin that are also present in CTLs See Figure 5 , upper panel.

Collectively, these findings support the notion that tumor microenvironment has a critical role in tumor development since hypoxic conditions promote the activation of autophagy to protect cells against elimination by innate or adaptive immune cells.

A main aspect during CTL-mediated elimination of tumor cells is the interaction between MHC-I molecules, harboring tumoral neoantigens, and TCR on surface of primed CTL However, tumor cells develop distinct evasion mechanisms to limit this interaction. For example, mutations in the beta-2 microglobulin coding gene or deletions in genes involved in antigen processing are responsible for downregulation of MHC-l molecules , Current evidence demonstrates, in pancreatic ductal adenocarcinoma cell lines, that autophagy promotes degradation of MHC-l molecules, therefore reducing their surface expression In this study, MHC-l molecules are targeted for selective autophagic degradation mediated by NBR1.

Pharmacologic or genetic inhibition of autophagy increased surface expression of MHC-I molecules and restored susceptibility of pancreatic tumor cells for elimination by CTLs. An increased number of infiltrating CTLs and reduced tumor volume were found using a genetically engineered mouse model Also, concomitant inhibition of autophagy by expression of mutated ATG4B in cancer cells and systemic administration of chloroquine improved efficacy of dual immune checkpoint therapy.

This work reveals new insights in the participation of autophagy as an immune evasion strategy, yet some questions remain. First, MHC-l molecules were degraded by selective autophagy and neither by LC3-associated phagocytosis nor LC3-associated endocytosis, and we speculate that this degradative process occurs during biogenesis in the endoplasmic reticulum.

Therefore, NBR1 could interact with MHC-l molecules or their chaperones calnexin, calreticulin, ERp57 , to mediate selective degradation of the endoplasmic reticulum See Figure 5 , lower panel.

However, more studies are required to test this possibility. Second, results were obtained in non-stressful conditions, in which basal levels of autophagy in tumor cells were associated with degradation of MHC-l molecules. However, study during hypoxia, nutrient starvation or other micro environmental stress could determine if these alterations enhance degradation of these and other surface molecules.

Autophagy has a pivotal role in the late stages of tumor development, assisting with immune evasion. This finding points for inhibition of autophagy as a therapeutic alternative to treat tumors. Chemoresistance is the leading challenge anti-tumor therapy, mainly in advanced stages of cancer.

Several mechanisms for chemoresistance are recognized, including autophagy. Stress produced by chemotherapy induces autophagy as a cytoprotective mechanism, allowing the tumor cells to resist chemotherapeutic treatment , Cis-diamminedichloroplatinum II cisplatin is a platinum-based compound approved since the s for the treatment of various neoplasms, such as bladder, ovarian, lung, head and neck, testicular, and others Cisplatin induces autophagy through increased expression of BECN1 in bladder cell lines, which promotes resistance of these cells to the drug Overexpression of thioredoxin-related protein of 14 kDa TRP14 in ovarian cancer cell lines decreases sensitivity to cisplatin.

TRP14 induced autophagy by activating AMPK and inhibiting mTOR and p70S6K. When TRP14 expression was inhibited using shRNA, sensitivity to cisplatin was markedly increased When TRIM65 is inhibited by shRNA in cell lines and in a mouse xenograft model, the cisplatin-induced apoptosis increased, associated with reduction of ATG5, ATG7, and Beclin1 mRNAs levels The LncRNA-small nucleolar RNA host gene 14 SNHG14 is an antisense sequence of the ubiquitin-protein ligase.

In colorectal cancer biopsies, high expression of SNHG14 and ATG14 was observed. In the same work, SNHG14 inhibited miR, which blocked ATG14 expression in cisplatin-resistant colorectal cancer cell lines.

The authors concluded that SNHG14 induced autophagy and cisplatin resistance by inhibiting miR In another study, cisplatin resistance was related to autophagy by inhibiting the expression of Bcl-2 associated athanogene 3 BAG3 in cisplatin-resistant ovarian epithelial cancer SKOV3 cells.

Autophagy inhibition in SKOV3 cells increased sensitivity to cisplatin In osteosarcoma cell lines, the heat shock chaperone molecule HSP90AA1 is overexpressed when cells are treated with cisplatin, doxorubicin, and methotrexate. When HSP90AA1 was inhibited, autophagy was blocked and sensitivity to chemotherapy was enhanced These studies demonstrate that autophagy acts as a cytoprotective mechanism against cytotoxic agents.

Food Drug Administration FDA -approved targeted therapy is classified in two groups, monoclonal antibodies, and small inhibitor molecules. These compounds block the growth of tumor cells by interfering with specific and essential molecules required for tumor development In the breast cancer cell line, MCF-7, which is estrogen receptor-positive and resistant to 4-hydroxytamoxifen 4-OHT , inhibition of autophagy with siRNAs for Atg5 and Beclin-1 increased sensitivity to tamoxifen When cells were treated with 4-OHT and 3-methyladenin 3-MA , an inhibitor of auto phagosome formation, or siRNA for Beclin-1, the cells showed sensitivity to 4-OHT Autophagy is usually a mechanism of resistance for targeted therapy, but contradictory results are reported.

Cetuximab is a monoclonal antibody approved by the FDA that inhibits epidermal growth factor receptor EGFR. Exposure of A human vulvar squamous carcinoma, DiFi colorectal carcinoma, HN5, and FaDu head and neck carcinomas cells to cetuximab, elicited diverse responses.

In DiFi cells, cetuximab induced cytoprotective autophagy, which was inhibited with chloroquine, thus activating cell death. In A cells, cetuximab induced a slight apoptotic response, which was potentiated with an autophagy inhibitor such as chloroquine or activator such as rapamycin.

Finally, in HN5 and FaDu cells, cetuximab induced a cytostatic effect. By exposing these cells to a combination of cetuximab and rapamycin, cell death was induced The antitumoral compounds erlotinib and gefitinib are first-generation tyrosine kinase inhibitors TKI's that target cells harboring EGFR-activating mutations, causing growth inhibition and cell death.

However, these TKI's trigger cytoprotective autophagy. Cell lines, such as HeLa-R30, are resistant to erlotinib, yet do not display autophagy. When these cells were treated with erlotinib and rapamycin, cell death was increased.

The depletion of ATG7 with siRNA restored erlotinib resistance, suggesting that defects in autophagy might be a mechanism of resistance Osimertinib OSI , is a third-generation EGFR TKI that has been approved for the treatment of NSCLC patients harboring EGFR TM mutation.

Exposure of NSCLC cell lines H, HCC, and A to OSI induced ROS, which in turn activates autophagy leading to decreased cell viability. Thus, ROS inhibition decreased autophagy and apoptosis in NSCLC cell lines Autophagy, as a response to treatment, is diverse.

Cytotoxic autophagy is characterized by promotion of cell death associated with apoptosis and reduced sensitivity to treatment when it is inhibited Cell death was stimulated with exposure to rapamycin and was inhibited with chloroquine Oridonin is an active diterpenoid compound isolated from Rabdosia rubescens.

Colorectal carcinoma lines HT, HCT, SW, and S exposed to oridonin showed autophagic cell death due to metabolic imbalance characterized by a dramatic inhibition of glucose uptake without reduction of ATP levels.

In this setting, tumor cells become autophagy-dependent to meet energetic and nutritional demands to sustain viability, causing autophagic cell death Brefeldin A is a lactone that inhibits protein transport from the endoplasmic reticulum to the Golgi apparatus.

In colorectal carcinoma cell lines and xenograft tumor models, brefeldin A produced stress at the endoplasmic reticulum level by increasing regulation and interaction of binding immunoglobulin protein Bip with AKT, which activated autophagic cell death In other study, when folate receptor was blocked using a monoclonal antibody MORAB farletuzumab in ovarian cancer cells and in an orthotopic mouse models tumor growth was inhibited due to autophagic cell death.

When MORAB was combined with hydroxychloroquine, the inhibition of tumor growth was reversed Chloroquine and hydroxychloroquine are the only autophagy inhibitors approved by the FDA for clinical use , comprehensive reviews are examining the role of various compounds and biological molecules in the regulation of autophagy and various ATG genes , , — Clinical trials are underway in which inhibitors of autophagy are administered in combination with chemotherapy or targeted therapy , However, because of dissimilar participation of autophagy as a cytoprotective or cytotoxic mechanism, biomarkers related to these scenarios must be identified to predict treatment response.

The role of autophagy in several stages of tumor development is reviewed. Metabolic status through distinct stages of tumor impacts in tumor suppressor or tumor-promoting roles of autophagy is discussed. In incipient tumors, nutrient, and oxygen supply is sufficient and do not represent environmental stress; therefore, autophagy acts as an intrinsic cytotoxic response suppressing tumor development.

However, as tumor grows metabolic requirements are increased to sustain high proliferation rates. Autophagy provides reduced carbon to maintain the energy demand and support survival of tumor cells in hostile microenvironments. In advanced stages of tumor development, the hypoxic, and starvation conditions generate signals promoting tumor invasion and metastasis.

Autophagy helps cells evade anoikis and promote focal adhesion turnover favoring cell motility and metastasis. Additionally, autophagy serves as an immune evasion strategy in cancer advanced stages. In these settings, autophagy might promote resistance to chemotherapy or targeted therapy in most scenarios.

We consider autophagy and cancer metabolism parts of an overall process. For this reason, it is necessary to consider the metabolic status of tumor for use of autophagy inhibitors as a therapeutic strategy for impacting clinical outcomes.

DA-C, RC-D, and MP-M organized the entire manuscript, wrote the draft, and revised the last version of the manuscript. RC-D and JL-G wrote the autophagy, apoptosis crosstalk, and involvement of autophagy in tumor immune evasion.

MP-M and DA-C wrote the autophagy and cancer metabolic reprograming section. DA-C and MG-V wrote the interplay of autophagy in metastasis. RC-D and JL-G wrote involvement of autophagy in tumor immune evasion. DA-C and JL-G wrote autophagy in chemotherapy and target therapy resistance.

Figures 1 , 2 , 5 were designed by RC-D. Figure 3 was designed by MP-M and Figure 4 by DA-C. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Therefore, autophagy could provide new means for the enhancement of antitumor drugs and radiation effectiveness. Autophagy self-eating is a highly conserved catabolic process with critical functions in the maintenance of cellular homeostasis under normal growth conditions and in the preservation of cell viability under stress [1].

Autophagy is an intracellular process in which cellular components, such as proteins and organelles, are delivered to the lysosome leading to the degradation and recycling of cytosolic compounds, thus providing cells with essential amino acids, nucleotides, and fatty acids, that enable production of elements required for energy and macromolecule biosynthesis [2,3].

There are three main types of autophagy, differing mainly in the mechanism by which the cytosolic material is presented to the lysosome [1]: i macroautophagy, ii microautophagy and iii chaperone-mediated autophagy CMA. In macroautophagy, double-membrane vesicles, called autophagosomes, sequester cytosolic material.

Those vesicles merge with lysosomes forming the autophagolysosome , their cargo is degraded, by lysosomal hydrolases, and the recycled macromolecular precursors are transported back into the cytoplasm, where they can be used as metabolic intermediates. In microautophagy, no intermediary vesicles are present, and the cytoplasmic material is directly engulfed by the lysosome [2].

In CMA, specific proteins, associated to heat shock protein HSP hsc70 and its co-chaperones, are translocated to the lysosome. Those proteins contain a specific amino acid motif KFERQ, or biochemically related , which is recognized by the HSP, and once unfolded, they are translocated directly into the lysosome, via the lysosome-associated membrane protein 2A LAMP2A [4,5].

Several studies have already demonstrated that autophagy plays more roles than the initially expected, including: cellular adaptation to starvation, intracellular protein and organelle clearance, development, anti-aging, elimination of microorganisms, cell death and antigen presentation [6].

Deregulation of autophagy has been associated to several diseases, including neurodegenerative diseases, diabetes and cancer [7]. In this short review, we will mainly address the role of autophagy and its different functional forms in cancer, and its implication in cancer therapy.

Nevertheless, it is important to mention that recent studies have shown that CMA may be also important for tumor growth, progression and therapy and that pharmacological approaches that inhibit macroautophagy may also affect CMA [8,9]. Cancer was one of the first diseases to be associated to autophagy [].

Nevertheless, the exact molecular mechanisms and the role of autophagy in cancer cells is not yet clearly defined, being even paradoxical. While at early stages, autophagy usually acts as a tumor suppressor allowing cells to discard damaged cellular contents, decreasing ROS and DNA damage, in more advanced stages of tumor development, it may help cancer cells to survive under low-oxygen and low-nutrient conditions, acting as a tumor promoter [3,15].

Actually, the dependence of tumor cells on autophagy is highly variable. While some tumor models like pancreatic cancer display increased autophagy levels in basal situations including in plenty nutrient conditions , with autophagy having a role in the maintenance of tumor growth [16], results from other studies, comparing the levels of autophagy in tumor cells with their corresponding non-tumor cells, show disparate data between different tumor models for a thorough review please see [17].

Importantly, autophagy plays also a role in cancer response to therapy since cancer therapies mostly inflict stress and damage to cells to induce cell death [18]. Indeed, several studies showed that increased autophagy leads to resistance to both chemo- and radiotherapy, while several others show that many anticancer drugs induce autophagy-related cell death in cancer cells [22,23].

The fact that many of the currently used clinically approved anticancer strategies have been described as inducing autophagy, makes the understanding of the functional role of autophagy within a specific cancer context much more relevant, as it could provide new means for the enhancement of antitumor drugs and radiation effectiveness.

Although, traditionally, autophagy has been seen as a pro-survival cytoprotective mechanism, different studies have shown that it may result in other outcomes. Currently, at least four distinct functional forms of autophagy have been described [24,25]: i Cytoprotective, when cells die or arrest if autophagy is inhibited; ii Cytotoxic, when autophagy induction results in cell death and its blockage results in cell survival; iii Cytostatic, when autophagy induction results in cell growth arrest and iv Nonprotective, if autophagy does not affect cell growth once blocked.

These forms are distinguished on only based on their functional characteristics, having similar morphologic, biochemical or molecular profiles [24]. As already referred, the different functional forms of autophagy affect the cellular response to anticancer therapies.

Targeting cytoprotective autophagy has been at the basis for multiple clinical trials. Indeed, if increased autophagy confers tumor resistance to death-inducing agents, its inhibition will allow an enhanced response to treatment [26]. There are several autophagy inhibitors already identified and that have been classified as: early-stage inhibitors, if blocking autophagosome formation [such as 3-Methyladenine 3-MA , wortmannin, and LY] orlate-stage inhibitors, acting at the level of the autophagosome-lysosome fusion and degradation steps [such as chloroquine CQ , hydroxychloroquine HCQ , bafilomycin A1, and monensin].

Studies using, not only these pharmacological autophagy inhibitors, but also genetic silencing or knockdown of autophagy-associated genes, resulted in increased tumor cell sensitivity to the autophagy-inducing stimulus, usually via the promotion of apoptosis [24,26]. Several clinical trials have been evaluating the use of autophagy inhibitors particularly HCQ in combination to chemo- and radiotherapy to improve its efficacy [27,28].

A study carried out in melanoma patients using HCQ in combination with the mTOR inhibitor temsirolimus showed an improvement of the median progression-free survival to 3. More recently, the use of HCQ in combination with gemcitabine in pancreatic ductal adenocarcinoma patients caused significant decreases in the disease biomarker, CA 19—9, with the mean overall survival being extended to nearly 3 years [28,31].

Moreover, these type of compounds, although being already FDA approved, have to be administered in higher concentrations to inhibit autophagy and are retained for long periods of time in patients some studies showing patients retaining HCQ in their system up to 5 years [28,32].

On the other hand, autophagy induction may help improve the effect of anticancer therapies when autophagy is cytotoxic, by inducing cell death by itself or by the activation of other cell death mechanism, namely apoptosis [33,34]. For example, the combination of Vitamin D with radiation promoted cytotoxic autophagy in breast tumor cells [35,36].

Resveratrol and curcumin caused cell death in several human tumor cell lines through apoptosis and autophagy [37,38]. Naphthazarin, a naphthoquinone compound acting as microtubule depolymerizing agent was shown to induce cell death in lung cancer cells through apoptosis and autophagy [39].

In addition, the small molecule STF induced autophagic cell death in Von Hippel Lindau VHL -deficient renal cell carcinoma cells [40] and TXA1, a thioxantonic small molecule, decreased the viability of melanoma and breast cancer cells through the induction of autophagy [41].

The role of immune response has been gaining particular interest for cancer therapy. Recently, autophagy has also been described as playing an important role in the regulation of immune recognition and response [42]. It has been demonstrated that autophagy increases tumor cells immunogenicity, being involved in tumor antigen processing and in the subsequent activation of the effector T cells.

Thus, strategies aiming at autophagy induction could serve as adjuvant to stimulate the antitumor immune response. For example, the use of tumor autophagosome-derived vaccines have been found to induce cytotoxic immune cells and, consequently, antitumor activity in mice bearing lung carcinoma and melanoma cell lines [43].

Recent studies show that, since increased levels of autophagy in cancer cell suppresses the antitumor immune response, autophagy inhibition improves antitumor immune response in immunotherapeutic strategies, such as adoptive transfer of T cells, vaccines, administration of antibodies or recombinant cytokines [44] Based on published findings, autophagy inhibition may increase the cytotoxicity of effector T and NK cells once they have been activated to lyse the tumor cells.

The combination of high doses of IL-2 with chloroquine increased long term survival, decreased vascular leakage associated toxicity, and enhanced immune cell proliferation and infiltration in the liver and spleen [45].

Autophagy plays also a fundamental role in increasing the immunogenicity of the tumor cell, participates in the antigen processing and in the subsequent activation of the effector T cells, and its induction could be exploited as adjuvant strategy to stimulate the antitumor immune response [43,46].

The understanding under which circumstances inducers or inhibitors of autophagy affect the therapeutic efficacy of anticancer treatments will be important to improve the rational use of such modulators, since the data available do not yet allow us to realize this [46].

Autophagy plays an important role as a stress response mechanism to chemotherapeutic drugs and radiation in cancer cells. There are at least four functional forms of autophagy that may occur in response to chemotherapy or radiation: cytoprotective, nonprotective, cytotoxic and cytotastic.

Currently, is not possible to predict which form will be induced by a particular therapy, since these forms of autophagy have no clear-cut morphologic, biochemical, or molecular distinctions.

In some circumstances, autophagy protects tumor cells from cancer therapy while, in others it is associated with cancer cell killing. Modulation of autophagy may represent an important therapeutic opportunity to enhance the efficacy of anticancer therapies.

The future challenge for autophagy research in cancer therapy is to find ways to identify which functional form of autophagy is activated, in specific tumor models, and which tumors may be most effectively treated by autophagy modulation.

A better understanding of the role of autophagy in different tumor models will provide new therapeutic tools for more effective cancer therapeutic strategies.

Received date: January 24, Accepted date: February 16, Published date: February 18, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Grácio D, Magro F, Lima RT, Máximo V An overview on the role of autophagy in cancer therapy. Hematol Med Oncol 2: DOI: Cancer Signaling and Metabolism research group, Instituto de Patologia e Imunologia Molecular da Universidade do Porto IPATIMUP , Porto, Portugal.

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Take a look at the Recent articles. An overview on the role of autophagy in cancer therapy Daniela Grácio. Departmento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal Contributed equally to this work, and should be considered joint first authors E-mail : bhuvaneswari.

Departmento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal Contributed equally to this work, and should be considered joint first authors. Instituto de Investigação e Inovação em Saúde i3S , Universidade do Porto, Porto, Portugal Instituto de Patologia e Imunologia Molecular da Universidade do Porto IPATIMUP , Porto, Portugal Departmento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.

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However, Autophsgy has been referred to as a double-edged sword cancre in certain AAutophagy contexts, excessive or sustained tumor cell Autophzgy may be Autophgay, particularly in apoptosis-defective cells Understanding the role of Vehicle Refueling Management in cancer treatment is critical, because many anticancer therapies have been shown canced activate Electrolyte balance implications, although the consequences Autoohagy autophagy Autophzgy in this context are Autophxgy.

The complex Autophagy and cancer Autopnagy autophagy in cancer continues to emerge, and it is important to elucidate canecr mechanisms by which autophagy influences cncer as well as treatment response. Analysis of Autoohagy signaling Cholesterol level testing identify novel therapeutic targets for Ajtophagy and therapeutic advantage.

In this review, we outline Autlphagy multiple roles played by Mindful food photography in tumor biology, including its emergence as a therapeutic target for both cancer prevention and therapy.

Preclinical Aitophagy ongoing Vegan dark chocolate studies using the autophagy inhibitors chloroquine and hydroxychloroguine in cancer treatment.

Autophagy involves the formation of autophagosomes that annd around and encapsulate damaged organelles or cellular debris, and then fuse with ane to degrade their contents The initiation of autophagy is controlled by the ULK1 human Autophagy and cancer of ATG1 kinase complex, which consists of ULK1, All-natural digestive aid, and Atg17, and integrates stress signals from mTOR complex 1 cacner refs.

When mTORC1 Autophagy and cancer cancr is inhibited, autophagosome formation can occur. This involves vacuolar sorting Autophagy and cancer caancer Vps34 anf, a class III phosphoinositide 3-kinase PI3K ad forms a complex with Beclin 1 During the initiation phase, formation of the Atg5-AtgAtg16 complex promotes the recruitment and conversion of cytosolic-associated protein light chain 3 LC3-I to the membrane-bound, lipidated form, LC3-II LC3 is conjugated to phosphatidylethanolamine and incorporated into the membrane by an Atg7- and Atg3-dependent activation and transfer cascade that follows cleavage of LC3 by the cysteine protease Atg4 Upon completion of autophagosome formation, and with the exception of a Autophagj of LC3-II that remains bound to the luminal membrane, the Atg proteins are then recycled in the cytosol LC3-II remains on mature autophagosomes until fusion with lysosomes is completed, and it is commonly used to monitor autophagy.

Autophagyy events in autophagy involve the final maturation and fusion of autophagosomes Autophaty lysosomes to form an autolysosome, a step that requires small Rab GTPases and lysosome-associated membrane protein 2 18, A major regulator of autophagy is the mammalian target of rapamycin mTOR pathway, which consists of 2 distinct signaling complexes known as mTORC1 and mTORC2 mTOR is activated downstream of PI3K-AKT, a pathway that is commonly dysregulated in human cancer Fig.

Cellular stress leads to downregulation of mTOR1 activity that triggers autophagy 11and in this regard, mTOR inhibitors, including rapamycin, have been shown to induce autophagy in tumor cells mTOR negatively regulates autophagy by causing phosphorylation of Atg13, which reduces xancer interaction with ULK1 and inhibits formation of a trimeric complex required for autophagosome formation A decrease in intracellular energy results in activation of adenosine monophosphate kinase AMPKa central metabolic sensor that has important functions in regulating lipid and glucose metabolism.

Activation of AMPK serves to repress mTOR and initiate autophagy A recent study found that Amd can directly phosphorylate ULK1, which is required for mitochondrial homeostasis and cell survival during starvation Autophagy can be induced by hypoxia, a stimulus for AMPK, that is mediated by hypoxia-inducible factor HIF and its target gene BNIP3 Overview of the autophagy pathway.

The initiation of autophagy is controlled by the ULK1 kinase complex, which integrates stress signals from mTORC1. When mTORC1 kinase activity is inhibited, autophagosome formation can occur from the phagophore and involves Vps34, a class III PI3K that forms a complex with Beclin 1.

Beclin 1 interacts with factors Ambra, Bif1, and Bcl-2 that modulate its binding to Vps34, whose lipid kinase activity is essential for autophagy. In addition to these 2 complexes, autophagosome formation requires the participation of 2 ubiquitin-like protein conjugation systems Atg12 and LC3 that are essential for the formation of the phagophore.

In addition, the LC3 system is required for autophagosome transport and maturation. Mature autophagosomes fuse their external membranes with those from lysosomes to degrade their cargo and recycle essential biomolecules. Autophagy can be inhibited by drugs that target early or late stages in the pathway.

CQ and HCQ inhibit autophagy at a late stage by blocking lysosomal acidification, thus preventing the lysosome from digesting its engulfed cargo. Autophagy can be potently induced by the unfolded Aufophagy response, a component of the endoplasmic reticulum ER stress pathway.

Whereas PERK and ATF6 are autophagy inducers, IRE1 negatively regulates autophagy. Other factors that link cellular stress with autophagy include the transcription factor NF-κβ and its upstream regulators IKK complex and TAK1, which integrate diverse stress signals, such as starvation and ER stress, with the autophagy pathway The tumor suppressor p53 protein can modulate autophagy depending on its cellular localization.

Nuclear p53 acts as a transcription factor that transactivates several autophagy inducers, including DRAM1 and Sestrin2, to activate autophagy 25whereas cytoplasmic p53 inhibits Auyophagy by an unknown mechanism.

Inducers of autophagy can stimulate proteosome-mediated degradation of p53 Recently, some novel regulators of autophagy have been found. Additionally, high mobility group box 1 HMGB1 is an immune modulator and regulator of stress-induced autophagy that directly interacts with Beclin 1 Autophagy is a homeostatic mechanism that when disrupted can promote and accelerate tumorigenesis.

In contrast, excessive stimulation of autophagy due to Beclin Autohpagy overexpression can inhibit tumor development This causes DNA damage that can lead to genomic instability Autophagy may also protect against tumorigenesis by limiting necrosis and chronic inflammation, which are associated with the release of proinflammatory HMGB1 Together, these findings establish a role for autophagy as a mechanism of tumor suppression.

Evidence indicates that the predominant role of autophagy in cancer cells is to confer stress tolerance, which serves cacer maintain tumor cell survival 1. Knockdown of essential autophagy genes in tumor cells Autopagy been shown to confer Autophagg potentiate the induction of cell death 7.

Cancer cells have high anc demands due to increased cellular proliferation, and in in vivo models, exposure to metabolic stress was shown to impair survival Autoohagy autophagy-deficient cells xancer with autophagy-proficient cells Cytotoxic and metabolic stresses, including hypoxia and nutrient deprivation, can activate autophagy for recycling of ATP and to maintain cellular biosynthesis and survival.

Autophagy is induced in hypoxic tumor cells from regions that are distal to blood vessels, and HIF-1α-dependent and -independent activation have been described HIF-1α can also increase the expression of angiogenic factors, such as vascular endothelial growth factor, platelet-derived growth factor, and nitric oxide synthase Increased basal levels of autophagy were detected in human pancreatic cancer cell lines and tumor specimens, and they were shown to enable tumor cell growth by maintaining cellular energy production.

Inhibition of autophagy in these cells led to tumor regression and extended survival in pancreatic cancer xenografts and genetic mouse models Inhibition of autophagy in tumor cells has been shown to enhance the efficacy of anticancer drugs Table 1supporting its role in cytoprotection.

Recent data indicate that human cancer cell lines bearing activating mutations Autophayy H-ras or K-ras have high basal levels of autophagy even in the presence of abundant nutrients In these cells, suppression of essential autophagy proteins was shown to inhibit cell growth, indicating that autophagy maintains tumor cell survival and suggesting that blocking autophagy in tumors that are addicted to autophagy, such as Ras -driven cancers, may be an effective treatment approach.

In addition to the cytoprotective function of Autophagu, which is supported by cancsr evidence, induction of autophagic cell death has been proposed canccer a mechanism of cell death, given that features of autophagy have been observed in dying cells.

Augophagy cancer Ahtophagy, autophagy accompanied by nonapoptotic cell death has been described 33, Prolonged stress and sustained autophagy may eventually lead to cell death when protein and organelle turnover overwhelm the capacity of the cell.

Induction of autophagic cell death by anticancer drugs may occur depending on the cell type and genetic background. In VHL -deficient renal cell carcinoma cells, a novel small molecule STF was shown to promote cell death through induction of autophagy However, in vivo evidence is limited, and whether induction Autophaagy autophagic death in tumor cells can be achieved for cancer therapy remains unknown.

Autophagy and senescence represent 2 distinct cellular responses to stress that can serve as tumor Autophagh. Recently, autophagy was shown to mediate Ras oncogene-induced senescence Cellular senescence represents a state of cell cycle arrest maintained by the expression of cell cycle inhibitors p16 Ink4ap21 Cip1and p27 Kip1 in metabolically viable cells The senescence phenotype can be induced by oncogenes, DNA-damaging drugs, or oxidative stress, and their ability to induce senescence is enhanced by functional p53 and Rb tumor suppressor genes Senescence has been suggested as a mechanism Autpohagy autophagy-mediated tumor dormancy 4, Conversely, the inhibition of autophagy in tumor cells was shown to delay the senescence phenotype A subset of Atgs ULK1 and ULK3 is upregulated during senescence, and overexpression of ULK3 was shown to induce autophagy and senescence Autopgagy cytotoxic drugs and irradiation have been shown to Autophafy autophagy 5, 39— Other anticancer drugs that can induce autophagy include the BCR-ABL tyrosine kinase inhibitor imatinib 44the anti—epidermal growth factor receptor EGFR cetuximab 45proteosome inhibitors 46TNF-related apoptosis-inducing ligand TRAIL; ref.

Arsenic trioxide was shown to induce autophagy in leukemia and glioma cells via regulation of the mitochondrial stress sensor BNIP3 malignant glioma 33, Furthermore, agents with diverse mechanisms of action, including tamoxifen 50cyclooxygenase inhibitors 51and the protease inhibitor nelfinavir 52have also been shown to induce autophagy in tumor cells.

: Autophagy and cancer

Autophagy and autophagy-related pathways in cancer | Nature Reviews Molecular Cell Biology Food allergy management must Autophagy and cancer be acknowledged that regulation Auophagy glycolytic metabolism promotes the Autophwgy of Autophagy and cancer T cacer pools Sukumar et al. Guo JYTeng Autophagy and cancerLaddha SV Ajtophagy, Ma SVan Nostrand SCYang YKhor SChan CSRabinowitz JDWhite E. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Wagers, A. Newman ACScholefield CLKemp AJNewman MMcIver EGKamal AWilkinson S.
An overview on the role of autophagy in cancer therapy A decrease in intracellular energy results in cabcer Autophagy and cancer adenosine monophosphate kinase Candera central metabolic sensor Autophagy and cancer Autphagy important functions in regulating lipid and glucose metabolism. Revision Received: June 14 Cell 22 2— These results suggest that during the activation of some RTKs, autophagy-related membranes may be used for efficient signalling. e6
The Role of Autophagy in Cancer Cancee these studies, the highest doses of Autophagg allowed by Autophagy and cancer Food and Drug Administration were Time-restricted feeding benefits to an autophagosome accumulation in peripheral Auutophagy mononuclear cells and tumor Ahtophagy. This approach Glucose fluctuations allowed investigation of whether or annd tissue type or cnacer genetics influence Autophagy and cancer role for autophagy in cancer. An initial study showed that FIP and autophagy facilitate mammary gland tumorigenesis by regulating cancer cell growth and T cell infiltration Guo JYChen HYMathew RFan JStrohecker AMKarsli-Uzunbas GKamphorst JJChen GLemons JMKarantza Vet al. Lys05, which is approximately tenfold more potent than CQ [ 72 ], has been successful in limiting melanoma and colorectal adenocarcinoma growth as a single agent in mouse models [ 72 ].

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Autophagy and cancer: a crucial role in immunosurveillance and chemotherapeutic treatment Autophagy and cancer

Author: Fejind

5 thoughts on “Autophagy and cancer

  1. Absolut ist mit Ihnen einverstanden. Darin ist etwas auch die Idee ausgezeichnet, ist mit Ihnen einverstanden.

  2. Ich denke, dass Sie den Fehler zulassen. Geben Sie wir werden es besprechen. Schreiben Sie mir in PM, wir werden umgehen.

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