Autophagy in malignant transformation and cancer progression
2015; Springer Nature; Volume: 34; Issue: 7 Linguagem: Inglês
10.15252/embj.201490784
ISSN1460-2075
AutoresLorenzo Galluzzi, Federico Pietrocola, José Manuel Bravo‐San Pedro, Ravi K. Amaravadi, Eric H. Baehrecke, Francesco Cecconi, Patrice Codogno, Jayanta Debnath, David A. Gewirtz, Vassiliki Karantza, Alec Kimmelman, Sharad Kumar, Beth Levine, Maria Chiara Maiuri, Séamus J. Martin, Josef Penninger, Mauro Piacentini, David C. Rubinsztein, Hans‐Uwe Simon, Anne Simonsen, Andrew Thorburn, Guillermo Velasco, Kevin M. Ryan, Guido Kroemer,
Tópico(s)Extracellular vesicles in disease
ResumoReview23 February 2015free access Autophagy in malignant transformation and cancer progression Lorenzo Galluzzi Corresponding Author Lorenzo Galluzzi Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Search for more papers by this author Federico Pietrocola Federico Pietrocola Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author José Manuel Bravo-San Pedro José Manuel Bravo-San Pedro Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Ravi K Amaravadi Ravi K Amaravadi Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA Search for more papers by this author Eric H Baehrecke Eric H Baehrecke Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA Search for more papers by this author Francesco Cecconi Francesco Cecconi Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark IRCCS Fondazione Santa Lucia and Department of Biology, University of Rome Tor Vergata, Rome, Italy Search for more papers by this author Patrice Codogno Patrice Codogno Université Paris Descartes, Sorbonne Paris Cité, Paris, France Institut Necker Enfants-Malades (INEM), Paris, France INSERM, U1151, Paris, France CNRS, UMR8253, Paris, France Search for more papers by this author Jayanta Debnath Jayanta Debnath Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA Search for more papers by this author David A Gewirtz David A Gewirtz Department of Pharmacology, Toxicology and Medicine, Virginia Commonwealth University, Richmond, Virginia, VA, USA Search for more papers by this author Vassiliki Karantza Vassiliki Karantza Merck Research Laboratories, Rahway, NJ, USA Search for more papers by this author Alec Kimmelman Alec Kimmelman Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Search for more papers by this author Sharad Kumar Sharad Kumar Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia Search for more papers by this author Beth Levine Beth Levine Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA Search for more papers by this author Maria Chiara Maiuri Maria Chiara Maiuri Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Seamus J Martin Seamus J Martin Department of Genetics, Trinity College, The Smurfit Institute, Dublin, Ireland Search for more papers by this author Josef Penninger Josef Penninger Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria Search for more papers by this author Mauro Piacentini Mauro Piacentini Department of Biology, University of Rome Tor Vergata, Rome, Italy National Institute for Infectious Diseases IRCCS ‘Lazzaro Spallanzani’, Rome, Italy Search for more papers by this author David C Rubinsztein David C Rubinsztein Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK Search for more papers by this author Hans-Uwe Simon Hans-Uwe Simon Institute of Pharmacology, University of Bern, Bern, Switzerland Search for more papers by this author Anne Simonsen Anne Simonsen Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Search for more papers by this author Andrew M Thorburn Andrew M Thorburn Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA Search for more papers by this author Guillermo Velasco Guillermo Velasco Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University of Madrid, Madrid, Spain Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain Search for more papers by this author Kevin M Ryan Kevin M Ryan Cancer Research UK Beatson Institute, Glasgow, UK Search for more papers by this author Guido Kroemer Guido Kroemer Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Lorenzo Galluzzi Corresponding Author Lorenzo Galluzzi Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Search for more papers by this author Federico Pietrocola Federico Pietrocola Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author José Manuel Bravo-San Pedro José Manuel Bravo-San Pedro Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Ravi K Amaravadi Ravi K Amaravadi Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA Search for more papers by this author Eric H Baehrecke Eric H Baehrecke Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA Search for more papers by this author Francesco Cecconi Francesco Cecconi Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark IRCCS Fondazione Santa Lucia and Department of Biology, University of Rome Tor Vergata, Rome, Italy Search for more papers by this author Patrice Codogno Patrice Codogno Université Paris Descartes, Sorbonne Paris Cité, Paris, France Institut Necker Enfants-Malades (INEM), Paris, France INSERM, U1151, Paris, France CNRS, UMR8253, Paris, France Search for more papers by this author Jayanta Debnath Jayanta Debnath Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA Search for more papers by this author David A Gewirtz David A Gewirtz Department of Pharmacology, Toxicology and Medicine, Virginia Commonwealth University, Richmond, Virginia, VA, USA Search for more papers by this author Vassiliki Karantza Vassiliki Karantza Merck Research Laboratories, Rahway, NJ, USA Search for more papers by this author Alec Kimmelman Alec Kimmelman Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Search for more papers by this author Sharad Kumar Sharad Kumar Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia Search for more papers by this author Beth Levine Beth Levine Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA Search for more papers by this author Maria Chiara Maiuri Maria Chiara Maiuri Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Seamus J Martin Seamus J Martin Department of Genetics, Trinity College, The Smurfit Institute, Dublin, Ireland Search for more papers by this author Josef Penninger Josef Penninger Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria Search for more papers by this author Mauro Piacentini Mauro Piacentini Department of Biology, University of Rome Tor Vergata, Rome, Italy National Institute for Infectious Diseases IRCCS ‘Lazzaro Spallanzani’, Rome, Italy Search for more papers by this author David C Rubinsztein David C Rubinsztein Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK Search for more papers by this author Hans-Uwe Simon Hans-Uwe Simon Institute of Pharmacology, University of Bern, Bern, Switzerland Search for more papers by this author Anne Simonsen Anne Simonsen Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway Search for more papers by this author Andrew M Thorburn Andrew M Thorburn Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA Search for more papers by this author Guillermo Velasco Guillermo Velasco Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University of Madrid, Madrid, Spain Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain Search for more papers by this author Kevin M Ryan Kevin M Ryan Cancer Research UK Beatson Institute, Glasgow, UK Search for more papers by this author Guido Kroemer Guido Kroemer Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France INSERM, U1138, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France Search for more papers by this author Author Information Lorenzo Galluzzi 1,2,3,4,‡,‡, Federico Pietrocola1,2,3,‡, José Manuel Bravo-San Pedro1,2,3,‡, Ravi K Amaravadi5, Eric H Baehrecke6, Francesco Cecconi7,8, Patrice Codogno4,9,10,11, Jayanta Debnath12, David A Gewirtz13, Vassiliki Karantza14, Alec Kimmelman15, Sharad Kumar16, Beth Levine17,18,19, Maria Chiara Maiuri1,2,3, Seamus J Martin20, Josef Penninger21, Mauro Piacentini22,23, David C Rubinsztein24, Hans-Uwe Simon25, Anne Simonsen26, Andrew M Thorburn27, Guillermo Velasco28,29, Kevin M Ryan30,‡ and Guido Kroemer1,2,4,31,32,‡ 1Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France 2INSERM, U1138, Paris, France 3Gustave Roussy Cancer Campus, Villejuif, France 4Université Paris Descartes, Sorbonne Paris Cité, Paris, France 5Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA 6Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA 7Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark 8IRCCS Fondazione Santa Lucia and Department of Biology, University of Rome Tor Vergata, Rome, Italy 9Institut Necker Enfants-Malades (INEM), Paris, France 10INSERM, U1151, Paris, France 11CNRS, UMR8253, Paris, France 12Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA 13Department of Pharmacology, Toxicology and Medicine, Virginia Commonwealth University, Richmond, Virginia, VA, USA 14Merck Research Laboratories, Rahway, NJ, USA 15Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA 16Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia 17Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA 18Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA 19Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA 20Department of Genetics, Trinity College, The Smurfit Institute, Dublin, Ireland 21Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria 22Department of Biology, University of Rome Tor Vergata, Rome, Italy 23National Institute for Infectious Diseases IRCCS ‘Lazzaro Spallanzani’, Rome, Italy 24Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK 25Institute of Pharmacology, University of Bern, Bern, Switzerland 26Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway 27Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA 28Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University of Madrid, Madrid, Spain 29Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain 30Cancer Research UK Beatson Institute, Glasgow, UK 31Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France 32Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France ‡These authors contributed equally to this work ‡These authors share senior co-authorship *Corresponding author. Tel: +33 1 44277661; E-mail: [email protected] The EMBO Journal (2015)34:856-880https://doi.org/10.15252/embj.201490784 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy. Introduction Macroautophagy (herein referred to as autophagy) is a mechanism that mediates the sequestration of intracellular entities within double-membraned vesicles, so-called autophagosomes, and their delivery to lysosomes for bulk degradation (He & Klionsky, 2009). Autophagosomes derive from so-called phagophores, membranous structures also known as ‘isolation membranes’ whose precise origin remains a matter of debate (Lamb et al, 2013). Indeed, the plasma membrane, endoplasmic reticulum (ER), Golgi apparatus, ER-Golgi intermediate compartment (ERGIC), and mitochondria have all been indicated as possible sources for phagophores (Lamb et al, 2013). Upon closure, autophagosomes fuse with lysosomes, forming so-called autolysosomes, and their cargo is exposed to the catalytic activity of lysosomal hydrolases (Mizushima & Komatsu, 2011). The degradation products of the autophagosomal cargo, which includes sugars, nucleosides/nucleotides, amino acids and fatty acids, can be transported back to the cytoplasm and presumably re-enter cellular metabolism (Fig 1) (Rabinowitz & White, 2010; Galluzzi et al, 2013). Of note, the molecular machinery that mediates autophagy is evolutionary conserved, and several components thereof have initially been characterized in yeast (He & Klionsky, 2009). Figure 1. General organization of autophagic responsesAutophagy initiates with the progressive segregation of cytoplasmic material by double-membraned structures commonly known as phagophores or isolation membranes. Phagophores nucleate from the endoplasmic reticulum (ER), but several other membranous organelles have been shown to contribute to their elongation, including the Golgi apparatus, ER-Golgi intermediate compartment (ERGIC), plasma membrane, mitochondria and recycling endosomes. Completely sealed phagophores, which are known as autophagosomes, fuse with lysosomes to form autolysosomes. This promotes the activation of lysosomal hydrolases and hence causes the breakdown of the autophagosomal cargo. The products of these catabolic reactions reach the cytosol via transporters of the lysosomal membrane and are recycled by anabolic or bioenergetic circuitries. Download figure Download PowerPoint In physiological scenarios, autophagy proceeds at basal levels, ensuring the continuous removal of superfluous, ectopic or damaged (and hence potentially dangerous) entities, including organelles and/or portions thereof (Green et al, 2011). Baseline autophagy mediates a key homeostatic function, constantly operating as an intracellular quality control system (Mizushima et al, 2008; Green et al, 2011). Moreover, the autophagic flux can be upregulated in response to a wide panel of stimuli, including (but not limited to) nutritional, metabolic, oxidative, pathogenic, genotoxic and proteotoxic cues (Kroemer et al, 2010). Often, stimulus-induced autophagy underlies and sustains an adaptive response to stress with cytoprotective functions (Kroemer et al, 2010; Mizushima & Komatsu, 2011). Indeed, the pharmacological or genetic inhibition of autophagy generally limits the ability of cells to cope with stress and restore homeostasis (Mizushima et al, 2008; Kroemer et al, 2010). This said, regulated instances of cell death that causally depend on the autophagic machinery have been described (Denton et al, 2009; Denton et al, 2012b; Liu et al, 2013b; Galluzzi et al, 2015). The detailed discussion of such forms of autophagic cell death, however, is beyond the scope of this review. Autophagy is tightly regulated. The best characterized repressor of autophagic responses is mechanistic target of rapamycin (MTOR) complex I (MTORCI) (Laplante & Sabatini, 2012). Thus, several inducers of autophagy operate by triggering signal transduction cascades that result in the inhibition of MTORCI (Inoki et al, 2012). Among other effects, this allows for the activation of several proteins that are crucial for the initiation of autophagic responses, such as unc-51-like autophagy-activating kinase 1 (ULK1, the mammalian ortholog of yeast Atg1) and autophagy-related 13 (ATG13) (Hosokawa et al, 2009; Nazio et al, 2013). A major inhibitor of MTORCI is protein kinase, AMP-activated (PRKA, best known as AMPK), which is sensitive to declining ATP/AMP ratios (Mihaylova & Shaw, 2011). Besides inhibiting the catalytic activity of MTORCI, AMPK directly stimulates autophagy by phosphorylating ULK1 as well as phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3, best known as VPS34) and Beclin 1 (BECN1, the mammalian ortholog of yeast Atg6), two components of a multiprotein complex that produces a lipid that is essential for the biogenesis of autophagosomes, namely phosphatidylinositol 3-phosphate (Egan et al, 2011; Zhao & Klionsky, 2011; Kim et al, 2013). Autophagy also critically relies on two ubiquitin-like conjugation systems, both of which involve ATG7 (Mizushima, 2007). These systems catalyze the covalent linkage of ATG5 to ATG12 and ATG16-like 1 (ATG16L1), and that of phosphatidylethanolamine to proteins of the microtubule-associated protein 1 light chain 3 (MAP1LC3, best known as LC3) family, including MAP1LC3B (LC3B, the mammalian ortholog of yeast Atg8) (Mizushima, 2007). A detailed discussion of additional factors that are involved in the control and execution of autophagic responses can be found in Boya et al (2013). Importantly, autophagosomes can either take up intracellular material in a relatively non-selective manner or deliver very specific portions of the cytoplasm to degradation, mainly depending on the initiating stimulus (Weidberg et al, 2011; Stolz et al, 2014). Thus, while non-selective forms of autophagy normally develop in response to cell-wide alterations, most often of a metabolic nature, highly targeted autophagic responses follow specific perturbations of intracellular homeostasis, such as the accumulation of permeabilized mitochondria (mitophagy), the formation of protein aggregates (aggrephagy), and pathogen invasion (xenophagy) (Okamoto, 2014; Randow & Youle, 2014). Several receptors participate in the selective recognition and recruitment of autophagosomal cargoes in the course of targeted autophagic responses (Rogov et al, 2014; Stolz et al, 2014). The autophagy receptor best characterized to date, that is, sequestosome 1 (SQSTM1, best known as p62), recruits ubiquitinated proteins to autophagosomes by virtue of an ubiquitin-associated (UBA) and a LC3-binding domain (Pankiv et al, 2007). Owing to its key role in the preservation of intracellular homeostasis, autophagy constitutes a barrier against various degenerative processes that may affect healthy cells, including malignant transformation. Thus, autophagy mediates oncosuppressive effects. Accordingly, proteins with bona fide oncogenic potential inhibit autophagy, while many proteins that prevent malignant transformation stimulate autophagic responses (Morselli et al, 2011). Moreover, autophagy is involved in several aspects of anticancer immunosurveillance, that is, the process whereby the immune system constantly eliminates potentially tumorigenic cells before they establish malignant lesions (Ma et al, 2013). However, autophagy also sustains the survival and proliferation of neoplastic cells exposed to intracellular and environmental stress, hence supporting tumor growth, invasion and metastatic dissemination, at least in some settings (Kroemer et al, 2010; Guo et al, 2013b). Here, we discuss the molecular and cellular mechanisms accounting for the differential impact of autophagy on malignant transformation and tumor progression. Autophagy and malignant transformation In various murine models, defects in the autophagic machinery caused by the whole-body or tissue-specific, heterozygous or homozygous knockout of essential autophagy genes accelerate oncogenesis. For instance, Becn1+/− mice (Becn1−/− animals are not viable) spontaneously develop various malignancies, including lymphomas as well as lung and liver carcinomas (Liang et al, 1999; Qu et al, 2003; Yue et al, 2003; Mortensen et al, 2011), and are more susceptible to parity-associated and Wnt1-driven mammary carcinogenesis than their wild-type counterparts (Cicchini et al, 2014). Similarly, mice lacking one copy of the gene coding for the BECN1 interactor autophagy/beclin-1 regulator 1 (AMBRA1) also exhibit a higher rate of spontaneous tumorigenesis than their wild-type littermates (Cianfanelli et al, 2015). Mice bearing a systemic mosaic deletion of Atg5 or a liver-specific knockout of Atg7 spontaneously develop benign hepatic neoplasms more frequently than their wild-type counterparts (Takamura et al, 2011). Moreover, carcinogen-induced fibrosarcomas appear at an accelerated pace in autophagy-deficient Atg4c−/− mice (Marino et al, 2007), as do KRASG12D-driven and BRAFV600E-driven lung carcinomas in mice bearing lung-restricted Atg5 or Atg7 deletions, respectively (Strohecker et al, 2013; Rao et al, 2014). The pancreas-specific knockout of Atg5 or Atg7 also precipitates the emergence of KRASG12D-driven pre-malignant pancreatic lesions (Rosenfeldt et al, 2013; Yang et al, 2014). Several mechanisms can explain, at least in part, the oncosuppressive functions of autophagy. Proficient autophagic responses may suppress the accumulation of genetic and genomic defects that accompanies malignant transformation, through a variety of mechanisms. Reactive oxygen species (ROS) are highly genotoxic, and autophagy prevents their overproduction by removing dysfunctional mitochondria (Green et al, 2011; Takahashi et al, 2013) as well as redox-active aggregates of ubiquitinated proteins (Komatsu et al, 2007; Mathew et al, 2009). In addition, autophagic responses have been involved in the disposal of micronuclei arising upon perturbation of the cell cycle (Rello-Varona et al, 2012), in the degradation of retrotransposing RNAs (Guo et al, 2014), as well as in the control of the levels of ras homolog family member A (RHOA), a small GTPase involved in cytokinesis (Belaid et al, 2013). Finally, various components of the autophagic machinery appear to be required for cells to mount adequate responses to genotoxic stress (Karantza-Wadsworth et al, 2007; Mathew et al, 2007; Park et al, 2014). This said, the precise mechanisms underlying such genome-stabilizing effects remain elusive, implying that the impact of autophagy on DNA-damage responses may be indirect. Further investigation is required to shed light on this possibility. Autophagy is intimately implicated in the maintenance of physiological metabolic homeostasis (Galluzzi et al, 2014; Kenific & Debnath, 2015). Malignant transformation generally occurs along with a shift from a predominantly catabolic consumption of glycolysis-derived pyruvate by oxidative phosphorylation to a metabolic pattern in which: (1) glucose uptake is significantly augmented to sustain anabolic reactions and antioxidant defenses, (2) mitochondrial respiration remains high to satisfy increased energy demands; and (3) several amino acids, including glutamine and serine, become essential as a means to cope with exacerbated metabolic functions (Hanahan & Weinberg, 2011; Galluzzi et al, 2013). Autophagy preserves optimal bioenergetic functions by ensuring the removal of dysfunctional mitochondria (Green et al, 2011), de facto counteracting the metabolic rewiring that accompanies malignant transformation. Moreover, the autophagic degradation of p62 participates in a feedback circuitry that regulates MTORCI activation in response to nutrient availability (Linares et al, 2013; Valencia et al, 2014). Autophagy appears to ensure the maintenance of normal stem cells. This is particularly relevant for hematological malignancies, which are normally characterized by changes in proliferation or differentiation potential that alter the delicate equilibrium between toti-, pluri- and unipotent precursors in the bone marrow (Greim et al, 2014). The ablation of Atg7 in murine hematopoietic stem cells (HSCs) has been shown to disrupt tissue architecture, eventually resulting in the expansion of a population of bone marrow progenitor cells with neoplastic features (Mortensen et al, 2011). Along similar lines, the tissue-specific deletion of the gene coding for the ULK1 interactor RB1-inducible coiled-coil 1 (RB1CC1, best known as FIP200) alters the fetal HSC compartment in mice, resulting in severe anemia and perinatal lethality (Liu et al, 2010). Interestingly, murine Rb1cc1−/− HSCs do not exhibit increased rates of apoptosis, but an accrued proliferative capacity (Liu et al, 2010). The deletion of Rb1cc1 in murine neuronal stem cells (NSCs) also causes a functional impairment that compromises postnatal neuronal differentiation (Wang et al, 2013). However, this effect appears to stem from the failure of murine Rb1cc1−/− HNCs to control redox homeostasis, resulting in the activation of a tumor protein p53 (TP53)-dependent apoptotic response (Wang et al, 2013). Finally, Becn1+/− mice display an expansion of progenitor-like mammary epithelial cells (Cicchini et al, 2014). Of note, autophagy also appears to be required for the preservation of normal stem cell compartments in the human system. Indeed, human hematopoietic, dermal, and epidermal stem cells transfected with a short-hairpin RNA (shRNA) specific for ATG5 lose their ability to self-renew while differentiating into neutrophils, fibroblasts, and keratinocytes, respectively (Salemi et al, 2012). It has been proposed that autophagy contributes to oncogene-induced cell death or oncogene-induced senescence, two fundamental oncosuppressive mechanisms. The activation of various oncogenes imposes indeed a significant stress on healthy cells, a situation that is normally aborted through the execution of a cell death program (Elgendy et al, 2011), or upon the establishment of permanent proliferative arrest (cell senescence) that engages the innate arm of the immune system (Iannello et al, 2013). The partial depletion of ATG5, ATG7 or BECN1 limited the demise of human ovarian cancer cells pharmacologically stimulated to express HRASG12V from an inducible construct (Elgendy et al, 2011). Similarly, shRNAs specific for ATG5 or ATG7 prevented oncogene-induced senescence in primary human melanocytes or human diploid fibroblasts (HDFs) expressing BRAFV600E or HRASG12V (Young et al, 2009; Liu et al, 2013a). Accordingly, the overexpression of the ULK1 homolog ULK3 was sufficient to limit the proliferative potential of HDFs while promoting autophagy (Young et al, 2009). Moreover, both pharmacological inhibitors of autophagy and small-interfering RNAs targeting ATG5, ATG7 or BECN1 prevented spontaneous senescence in HDFs while preventing the degradation of an endogenous, dominant-neg
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