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• W3134787367 abstract "Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors. By better understanding how organelle-specific autophagy takes place and can be manipulated, it may be possible to go beyond the brute-force approach of trying to manipulate all autophagy in order to improve therapeutic targeting of this process in cancer. Beginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors. By better understanding how organelle-specific autophagy takes place and can be manipulated, it may be possible to go beyond the brute-force approach of trying to manipulate all autophagy in order to improve therapeutic targeting of this process in cancer. The recycling processes that deliver excess or damaged cytoplasmic material to lysosomes for degradation are one of three pathways: micro-autophagy, chaperone-mediated autophagy, and macro-autophagy. Macro-autophagy (hereafter referred to as autophagy) is a complex process that promotes both bulk and selective degradation of damaged proteins and organelles or spare molecules to generate macromolecular building blocks and fuel metabolic pathways (Dikic and Elazar, 2018Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy.Nat. Rev. Mol. Cell Biol. 2018; 19: 349-364Crossref PubMed Scopus (629) Google Scholar). Autophagy involves over 20 core autophagy proteins—encoded by ATG genes—that envelop cytoplasmic cargo within a double-membrane vesicle structure called the autophagosome (Suzuki et al., 2001Suzuki K. Kirisako T. Kamada Y. Mizushima N. Noda T. Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation.EMBO J. 2001; 20: 5971-5981Crossref PubMed Scopus (722) Google Scholar). After engulfment of the cargo, autophagosomes fuse with lysosomes, where pH-sensitive hydrolases mediate degradation of the engulfed material (Dikic and Elazar, 2018Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy.Nat. Rev. Mol. Cell Biol. 2018; 19: 349-364Crossref PubMed Scopus (629) Google Scholar). Selective autophagy occurs through targeting of specific cargos, including organelles, to autophagosomes. Micro-autophagy and chaperone-mediated autophagy are considered selective forms of autophagy that involve direct delivery mechanisms of targeted material to the lysosome (Anding and Baehrecke, 2017Anding A.L. Baehrecke E.H. Cleaning house: selective autophagy of organelles.Dev. Cell. 2017; 41: 10-22Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar; Mijaljica et al., 2011Mijaljica D. Prescott M. Devenish R.J. Microautophagy in mammalian cells: revisiting a 40-year-old conundrum.Autophagy. 2011; 7: 673-682Crossref PubMed Scopus (284) Google Scholar; Sahu et al., 2011Sahu R. Kaushik S. Clement C.C. Cannizzo E.S. Scharf B. Follenzi A. Potolicchio I. Nieves E. Cuervo A.M. Santambrogio L. Microautophagy of cytosolic proteins by late endosomes.Dev. Cell. 2011; 20: 131-139Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar; Kaushik and Cuervo, 2018Kaushik S. Cuervo A.M. The coming of age of chaperone-mediated autophagy.Nat. Rev. Mol. Cell Biol. 2018; 19: 365-381Crossref PubMed Scopus (257) Google Scholar). Selective autophagy has three distinct steps: designation, targeting and sequestration, and degradation. Designation occurs when a cargo receives a molecular tag for its recognition by the autophagy machinery. Ubiquitination often provides this signal in mammalian cells (Kim et al., 2008Kim P.K. Hailey D.W. Mullen R.T. Lippincott-Schwartz J. Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes.Proc. Natl. Acad. Sci. USA. 2008; 105: 20567-20574Crossref PubMed Scopus (388) Google Scholar; Rogov et al., 2014Rogov V. Dötsch V. Johansen T. Kirkin V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy.Mol. Cell. 2014; 53: 167-178Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar). Next, targeting and sequestration occur when designated cargos are delivered to autophagosomes by specific receptors, allowing the autophagosome to engulf and sequester cargo. Numerous autophagy cargo receptors (ACRs) have been identified in mammals, including SQSTM1/p62, NBR1, optineurin (OPTN), NDP52, TAX1BP, BNIP3-like (BNIP3L)/NIX, and TRIM proteins (Rogov et al., 2014Rogov V. Dötsch V. Johansen T. Kirkin V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy.Mol. Cell. 2014; 53: 167-178Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar; Mandell et al., 2014Mandell M.A. Jain A. Arko-Mensah J. Chauhan S. Kimura T. Dinkins C. Silvestri G. Münch J. Kirchhoff F. Simonsen A. et al.TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition.Dev. Cell. 2014; 30: 394-409Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). A key step in the formation of autophagosomes is the conjugation of the LC3/GABARAP family of proteins to the lipid, phosphatidylethanolamine (PE), which is mediated by the autophagy conjugation machinery including ATG3, ATG5, ATG7, and ATG12. Importantly, these conjugation events are frequently used as a method to monitor autophagy levels (the most common method to quantitate the amount of autophagy is to measure the rate of conjugation of LC3B to PE). A common way to block autophagy involves the inactivation by knockout or knockdown of a component of the conjugation machinery. These conjugation events are important for proper development of autophagosomes and the conjugated LC3 molecules on the inner autophagosome membrane serve as targets that are recognized by the ACRs. Then, fusion of the autophagosome with the lysosome takes place, followed by degradation of the inner autophagosome membrane, allowing lysosomal hydrolases access to degrade the cargo. Lastly, macromolecular precursors including amino acids, lipids, etc., resulting from degradation of the cargo are released to the cytoplasm to fuel metabolic pathways and to serve as substrates for the synthesis of new macromolecules. Autophagy can both promote and inhibit tumor growth in different contexts (White, 2015White E. The role for autophagy in cancer.J. Clin. Invest. 2015; 125: 42-46Crossref PubMed Scopus (641) Google Scholar; Amaravadi et al., 2019Amaravadi R.K. Kimmelman A.C. Debnath J. Targeting autophagy in cancer: recent advances and future directions.Cancer Discov. 2019; 9: 1167-1181Crossref PubMed Scopus (103) Google Scholar). For example, genetic inhibition of Atg5 or Atg7 showed that deletion of autophagy in tumor-prone mouse models following RAS pathway activation caused an increase in preneoplastic lesions and tumor incidence, indicating that autophagy protects against cancer development (Strohecker et al., 2013Strohecker A.M. Guo J.Y. Karsli-Uzunbas G. Price S.M. Chen G.J. Mathew R. Mcmahon M. White E. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors.Cancer Discov. 2013; 3: 1272-1285Crossref PubMed Scopus (238) Google Scholar; Rao et al., 2014Rao S. Tortola L. Perlot T. Wirnsberger G. Novatchkova M. Nitsch R. Sykacek P. Frank L. Schramek D. Komnenovic V. et al.A dual role for autophagy in a murine model of lung cancer.Nat. Commun. 2014; 5: 3056Crossref PubMed Scopus (248) Google Scholar; Rosenfeldt et al., 2013Rosenfeldt M.T. O'Prey J. Morton J.P. Nixon C. Mackay G. Mrowinska A. Au A. Rai T.S. Zheng L. Ridgway R. et al.p53 status determines the role of autophagy in pancreatic tumour development.Nature. 2013; 504: 296-300Crossref PubMed Scopus (412) Google Scholar; Yang et al., 2014Yang A. Rajeshkumar N.V. Wang X. Yabuuchi S. Alexander B.M. Chu G.C. Von Hoff D.D. Maitra A. Kimmelman A.C. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.Cancer Discov. 2014; 4: 905-913Crossref PubMed Scopus (246) Google Scholar). In these mice, it is likely that the defective autophagy process causes chronic tissue damage, leading to tumor-initiating inflammation (White et al., 2010White E. Karp C. Strohecker A.M. Guo Y. Mathew R. Role of autophagy in suppression of inflammation and cancer.Curr. Opin. Cell Biol. 2010; 22: 212-217Crossref PubMed Scopus (224) Google Scholar). Various other tumor-suppressive functions of autophagy have also been proposed, as autophagy plays an important role in tissue homeostasis. Most of these mechanisms likely affect tumor initiation and early steps in cancer progression, including removal of damaging reactive oxygen species (ROS)-inducing mitochondria, degradation of oncogenic viruses, maintenance of genomic stability, and a role in oncogene-induced senescence via degradation of the nuclear lamina (Levine and Kroemer, 2019Levine B. Kroemer G. Biological functions of autophagy genes: a disease perspective.Cell. 2019; 176: 11-42Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar; Wang et al., 2016Wang J. Fang Y. Yan L. Yuan N. Zhang S. Xu L. Nie M. Zhang X. Wang J. Erythroleukemia cells acquire an alternative mitophagy capability.Sci. Rep. 2016; 6: 24641Crossref PubMed Scopus (13) Google Scholar; Dou et al., 2015Dou Z. Xu C. Donahue G. Shimi T. Pan J.-A. Zhu J. Ivanov A. Capell B.C. Drake A.M. Shah P.P. et al.Autophagy mediates degradation of nuclear lamina.Nature. 2015; 527: 105-109Crossref PubMed Scopus (268) Google Scholar). However, it is important to note that it is possible to have mutations or expression of alternate splice variants of autophagy genes that negatively regulate autophagy (Wible et al., 2019Wible D.J. Chao H.P. Tang D.G. Bratton S.B. ATG5 cancer mutations and alternative mRNA splicing reveal a conjugation switch that regulates ATG12-ATG5-ATG16L1 complex assembly and autophagy.Cell Discov. 2019; 5: 42Crossref PubMed Scopus (6) Google Scholar), this seldom occurs in cancer (Lebovitz et al., 2015Lebovitz C.B. Robertson A.G. Goya R. Jones S.J. Morin R.D. Marra M.A. Gorski S.M. Cross-cancer profiling of molecular alterations within the human autophagy interaction network.Autophagy. 2015; 11: 1668-1687Crossref PubMed Scopus (57) Google Scholar). Later in disease progression, it is more common for oncogenic events to activate autophagy or enhance lysosomal biogenesis to withstand nutrient deprivation as well as prevent excessive accumulation of the toxic molecules discussed above (Amaravadi et al., 2019Amaravadi R.K. Kimmelman A.C. Debnath J. Targeting autophagy in cancer: recent advances and future directions.Cancer Discov. 2019; 9: 1167-1181Crossref PubMed Scopus (103) Google Scholar). Therefore, once a tumor becomes established, autophagy inhibition often results in less aggressive cancers. For example, pancreatic cancers have increased autophagy flux that contributes to their growth (Yang et al., 2011Yang S. Wang X. Contino G. Liesa M. Sahin E. Ying H. Bause A. Li Y. Stommel J.M. Dell'Antonio G. et al.Pancreatic cancers require autophagy for tumor growth.Genes Dev. 2011; 25: 717-729Crossref PubMed Scopus (839) Google Scholar) through multiple tumor-cell-intrinsic and nontumor-intrinsic mechanisms (Piffoux et al., 2021Piffoux M. Eriau E. Cassier P.A. Autophagy as a therapeutic target in pancreatic cancer.Br. J. Cancer. 2021; 124: 333-344Crossref PubMed Scopus (1) Google Scholar; Yang et al., 2018Yang A. Herter-Sprie G. Zhang H. Lin E.Y. Biancur D. Wang X. Deng J. Hai J. Yang S. Wong K.-K. Kimmelman A.C. Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms.Cancer Discov. 2018; 8: 276-287Crossref PubMed Scopus (103) Google Scholar). As such, mutations in autophagy genes would thwart the tumor’s rapid growth and metastasis and instead result in death or senescence. This increase in autophagy flux makes pancreatic cancer a strong candidate for therapeutic targeting of autophagy. Roles of autophagy in cancer and the potential of targeting autophagy as a therapeutic strategy for various cancers have been extensively reviewed (Mulcahy Levy et al., 2017Mulcahy Levy J.M. Zahedi S. Griesinger A.M. Morin A. Davies K.D. Aisner D.L. Kleinschmidt-Demasters B.K. Fitzwalter B.E. Goodall M.L. Thorburn J. et al.Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors.eLife. 2017; 6: e19671Crossref PubMed Scopus (75) Google Scholar; Galluzzi et al., 2015Galluzzi L. Pietrocola F. Bravo-San Pedro J.M. Amaravadi R.K. Baehrecke E.H. Cecconi F. Codogno P. Debnath J. Gewirtz D.A. Karantza V. et al.Autophagy in malignant transformation and cancer progression.EMBO J. 2015; 34: 856-880Crossref PubMed Scopus (687) Google Scholar; Amaravadi et al., 2019Amaravadi R.K. Kimmelman A.C. Debnath J. Targeting autophagy in cancer: recent advances and future directions.Cancer Discov. 2019; 9: 1167-1181Crossref PubMed Scopus (103) Google Scholar; Mulcahy Levy and Thorburn, 2020Mulcahy Levy J.M. Thorburn A. Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients.Cell Death Differ. 2020; 27: 843-857Crossref PubMed Scopus (25) Google Scholar; White, 2015White E. The role for autophagy in cancer.J. Clin. Invest. 2015; 125: 42-46Crossref PubMed Scopus (641) Google Scholar). Because tumors are established at the time of detection and treatment, autophagy inhibition would be effective for this stage of the disease. However, autophagy also has pro- and anti-metastatic effects. For example, autophagy can aid in the ability to endure environmental stress as well as promote an antitumor immune response or cell dormancy for migrating cancer cells {Kenific, 2010 #387}. Given these competing roles of autophagy in general, targeting organelle homeostasis rather than general autophagy processes could potentially be a more effective way to treat cancer by allowing more precision in the targeting of pro-tumor functions while avoiding antitumor-promoting functions of autophagy. In this review, we discuss how the role of autophagy in organelle homeostasis may affect tumor behavior. However, it is important to keep in mind that, although many studies propose critical roles for specific types of organelle-phagy in cancer cell behavior, such conclusions may be over simplified. In many of these studies, a component of the autophagy machinery, often a component of the conjugation machinery, is inhibited as a way to block organelle-specific autophagy. But such studies do not exclude the possibility that the biological effect depends not (only) on the loss of degradation of the specific organelle in question but also on the absence of degradation of other molecules or organelles. In addition, in many cases it remains possible that the effect is due to autophagy-independent functions of autophagy components (Galluzzi and Green, 2019Galluzzi L. Green D.R. Autophagy-independent functions of the autophagy machinery.Cell. 2019; 177: 1682-1699Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). Therefore, specific manipulation of organelle-specific autophagy pathways is required to confirm that a biological effect arises due to autophagy of that specific organelle. However, this may be difficult due to the redundancy of autophagy adaptors utilized across different types of organelle-targeted autophagy. Mitochondria are well known for their role in ATP generation (Green and Kroemer, 2004Green D.R. Kroemer G. The pathophysiology of mitochondrial cell death.Science. 2004; 305: 626-629Crossref PubMed Scopus (2622) Google Scholar) but they have several other functions that are intertwined with hallmarks of cancer (Giampazolias and Tait, 2016Giampazolias E. Tait S.W. Mitochondria and the hallmarks of cancer.FEBS Journal. 2016; 283: 803-814Crossref PubMed Scopus (0) Google Scholar). Mitochondria are vulnerable to damage from high levels of ROS, a byproduct of aerobic respiration that can also cause DNA mutations and protein damage/misfolding. Mitochondria are also involved in fatty acid synthesis, amino acid production, heme synthesis and iron–sulfur cluster biogenesis, and play an essential role in the execution of apoptosis by releasing cytochrome c (Wang and Youle, 2009Wang C. Youle R.J. The role of mitochondria in apoptosis.Annu. Rev. Genet. 2009; 43: 95-118Crossref PubMed Scopus (946) Google Scholar). As such, the clearance of mitochondria can have diverse effects on tumor development, growth, and progression. The autophagy-targeted degradation of mitochondria is accomplished by a selective form of autophagy, named mitophagy (Lemasters, 2005Lemasters J.J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging.Rejuvenation Res. 2005; 8: 3-5Crossref PubMed Scopus (741) Google Scholar) (Figure 1). Mitophagy can be initiated by stimuli that cause mitochondrial damage, such as hypoxia (Bellot et al., 2009Bellot G. Garcia-Medina R. Gounon P. Chiche J. Roux D. Pouyssegur J. Mazure N.M. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.Mol Cell Biol. 2009; 29: 2570-2581Crossref PubMed Scopus (858) Google Scholar; Zhang et al., 2008Zhang H. Bosch-Marce M. Shimoda L.A. Tan Y.S. Baek J.H. Wesley J.B. Gonzalez F.J. Semenza G.L. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.J. Biol. Chem. 2008; 283: 10892-10903Abstract Full Text Full Text PDF PubMed Scopus (1069) Google Scholar), chemical uncouplers (Narendra et al., 2008Narendra D. Tanaka A. Suen D.F. Youle R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.J. Cell Biol. 2008; 183: 795-803Crossref PubMed Scopus (2395) Google Scholar), or ROS (Frank et al., 2012Frank M. Duvezin-Caubet S. Koob S. Occhipinti A. Jagasia R. Petcherski A. Ruonala M.O. Priault M. Salin B. Reichert A.S. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner.Biochim Biophys Acta. 2012; 1823: 2297-2310Crossref PubMed Scopus (259) Google Scholar; Zhang et al., 2008Zhang H. Bosch-Marce M. Shimoda L.A. Tan Y.S. Baek J.H. Wesley J.B. Gonzalez F.J. Semenza G.L. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.J. Biol. Chem. 2008; 283: 10892-10903Abstract Full Text Full Text PDF PubMed Scopus (1069) Google Scholar). The best understood mechanism of mitophagy involves PTEN-induced putative kinase 1 (PINK1), a mitochondrially localized kinase, and Parkin, a cytosolic E3 ubiquitin ligase (Narendra et al., 2010Narendra D.P. Jin S.M. Tanaka A. Suen D.F. Gautier C.A. Shen J. Cookson M.R. Youle R.J. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.PLoS Biol. 2010; 8: e1000298Crossref PubMed Scopus (1636) Google Scholar), both of which are mutated in early-onset recessive Parkinson’s disease. A small portion of PINK1 is imported into mitochondria through two complexes: the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM23). While in the inner mitochondrial membrane, matrix processing peptidase (MPP) clips the intra-membrane section of PINK1 and the inner membrane protease PINK1/PGAM5-associated rhomboid-like protease (PARL) (Jin et al., 2010Jin S.M. Lazarou M. Wang C. Kane L.A. Narendra D.P. Youle R.J. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL.J. Cell Biol. 2010; 191: 933-942Crossref PubMed Scopus (692) Google Scholar). After cleavage and activation, PINK1 phosphorylates Parkin to increase its ubiquitin E3 ligase activity (Shiba-Fukushima et al., 2012Shiba-Fukushima K. Imai Y. Yoshida S. Ishihama Y. Kanao T. Sato S. Hattori N. PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy.Sci. Rep. 2012; 2: 1002Crossref PubMed Scopus (330) Google Scholar; Koyano et al., 2014Koyano F. Okatsu K. Kosako H. Tamura Y. Go E. Kimura M. Kimura Y. Tsuchiya H. Yoshihara H. Hirokawa T. et al.Ubiquitin is phosphorylated by PINK1 to activate parkin.Nature. 2014; 510: 162-166Crossref PubMed Scopus (736) Google Scholar), resulting in activation of Parkin and the addition of ubiquitin to various mitochondrial substrates, eventually forming ubiquitin chains on a variety of these proteins (Okatsu et al., 2015Okatsu K. Koyano F. Kimura M. Kosako H. Saeki Y. Tanaka K. Matsuda N. Phosphorylated ubiquitin chain is the genuine Parkin receptor.J. Cell Biol. 2015; 209: 111-128Crossref PubMed Scopus (137) Google Scholar). Several ACRs mediate Parkin-dependent mitophagy in mammalian cells: p62/SQSTM1, NDP52, OPTN, NIX, FUNDC1, BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), and TAX1BP1 (Lazarou et al., 2015Lazarou M. Sliter D.A. Kane L.A. Sarraf S.A. Wang C. Burman J.L. Sideris D.P. Fogel A.I. Youle R.J. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.Nature. 2015; 524: 309-314Crossref PubMed Google Scholar; Heo et al., 2015Heo J.M. Ordureau A. Paulo J.A. Rinehart J. Harper J.W. The PINK1-Parkin mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy.Mol. Cell. 2015; 60: 7-20Abstract Full Text Full Text PDF PubMed Google Scholar; Chen et al., 2016Chen M. Chen Z. Wang Y. Tan Z. Zhu C. Li Y. Han Z. Chen L. Gao R. Liu L. Chen Q. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy.Autophagy. 2016; 12: 689-702Crossref PubMed Google Scholar). These ARCs direct ubiquitinated mitochondria to phagophores by binding the ubiquitin molecules on the mitochondrial surface and LC3 family members on the inner autophagosome membrane via an LC3-interacting region (LIR) domain (Figure 1). Although cancer cells often do not express Parkin (Chang et al., 2017Chang J.Y. Yi H.S. Kim H.W. Shong M. Dysregulation of mitophagy in carcinogenesis and tumor progression.Biochim. Biophys. Acta Bioenerg. 2017; 1858: 633-640Crossref PubMed Scopus (24) Google Scholar; Zhang et al., 2020Zhang Z.L. Wang N.N. Ma Q.L. Chen Y. Yao L. Zhang L. Li Q.S. Shi M.H. Wang H.F. Ying Z. Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells.Acta Pharmacol. Sin. 2020; 41: 93-100Crossref PubMed Scopus (5) Google Scholar), they adopt similar mechanisms for removal of mitochondria, usually through alternate ubiquitin ligases (Villa et al., 2018Villa E. Marchetti S. Ricci J.E. No parkin zone: mitophagy without parkin.Trends Cell Biol. 2018; 28: 882-895Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). ARIH1 is a ubiquitin ligase that has the potential to promote mitophagy in the absence of Parkin in various types of cancer cells (Villa et al., 2017Villa E. Proïcs E. Rubio-Patiño C. Obba S. Zunino B. Bossowski J.P. Rozier R.M. Chiche J. Mondragón L. Riley J.S. et al.Parkin-independent mitophagy controls chemotherapeutic response in cancer cells.Cell Rep. 2017; 20: 2846-2859Abstract Full Text Full Text PDF PubMed Google Scholar). Similarly, autophagy and Beclin1 regulator 1 (AMBRA1) localizes to damaged mitochondria through LIR-motif-dependent interactions with LC3, promoting both Parkin-dependent and Parkin-independent mitochondrial degradation (Strappazzon et al., 2015Strappazzon F. Nazio F. Corrado M. Cianfanelli V. Romagnoli A. Fimia G.M. Campello S. Nardacci R. Piacentini M. Campanella M. Cecconi F. AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1.Cell Death Differ. 2015; 22: 419-432Crossref PubMed Google Scholar). This interaction enhances the mitochondrial localization of HECT, UBA, and WWE domain-containing E3 ubiquitin protein ligase 1 (HUWE1), which ubiquitinates mitofusin-2 (MFN2) to promote mitophagy after membrane depolarization (Di Rita et al., 2018Di Rita A. Peschiaroli A. D Acunzo P. Strobbe D. Hu Z. Gruber J. Nygaard M. Lambrughi M. Melino G. Papaleo E. et al.HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα.Nat. Commun. 2018; 9: 3755Crossref PubMed Scopus (67) Google Scholar). Mitophagy receptors, BNIP3 and NIX, can also trigger mitophagy in the absence of protein ubiquitination (Novak et al., 2010Novak I. Kirkin V. Mcewan D.G. Zhang J. Wild P. Rozenknop A. Rogov V. Löhr F. Popovic D. Occhipinti A. et al.Nix is a selective autophagy receptor for mitochondrial clearance.EMBO Rep. 2010; 11: 45-51Crossref PubMed Scopus (746) Google Scholar; Hanna et al., 2012Hanna R.A. Quinsay M.N. Orogo A.M. Giang K. Rikka S. Gustafsson Å.B. Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy.J. Biol. Chem. 2012; 287: 19094-19104Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar). All these mechanisms rely upon LC3 conjugation to selectively sequester mitochondria in the autophagosome. One major unanswered question is whether mitophagy can still occur in cancer cells when the autophagy apparatus is disabled as occurs when, as discussed below, we design experiments where we inactivate a component of the conjugation machinery in tumors. Because mitochondrial permeabilization is the key rate-limiting step in apoptosis, one obvious mechanism by which mitophagy might allow cancer cells to evade death is by removing mitochondria that could potentially be permeabilized to induce cell death. Degradation of dysfunctional mitochondria has been reported to promote cell survival by preventing the production or release of toxic byproducts such as ROS and cytochrome c that cause apoptosis (Galluzzi et al., 2006Galluzzi L. Larochette N. Zamzami N. Kroemer G. Mitochondria as therapeutic targets for cancer chemotherapy.Oncogene. 2006; 25: 4812-4830Crossref PubMed Scopus (287) Google Scholar; Colell et al., 2007Colell A. Ricci J.E. Tait S. Milasta S. Maurer U. Bouchier-Hayes L. Fitzgerald P. Guio-Carrion A. Waterhouse N.J. Li C.W. et al.GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation.Cell. 2007; 129: 983-997Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). Consistent with this, mitophagy has been reported to cause cancer cell resistance to radiation (Wang et al., 2016Wang J. Fang Y. Yan L. Yuan N. Zhang S. Xu L. Nie M. Zhang X. Wang J. Erythroleukemia cells acquire an alternative mitophagy capability.Sci. Rep. 2016; 6: 24641Crossref PubMed Scopus (13) Google Scholar), microtubule inhibitors (Wei et al., 2018Wei R. Cao J. Yao S. Matrine promotes liver cancer cell apoptosis by inhibiting mitophagy and PINK1/Parkin pathways.Cell Stress Chaperones. 2018; 23: 1295-1309Crossref PubMed Scopus (27) Google Scholar), doxorubicin (Zhang et al., 2012Zhang S. Liu X. Bawa-Khalfe T. Lu L.S. Lyu Y.L. Liu L.F. Yeh E.T. Identification of the molecular basis of doxorubicin-induced cardiotoxicity.Nat. Med. 2012; 18: 1639-1642Crossref PubMed Scopus (875) Google Scholar; Yan et al., 2017Yan C. Luo L. Guo C.Y. Goto S. Urata Y. Shao J.H. Li T.S. Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells.Cancer Lett. 2017; 388: 34-42Crossref PubMed Google Scholar), cisplatin, and etoposide (Villa et al., 2017Villa E. Proïcs E. Rubio-Patiño C. Obba S. Zunino B. Bossowski J.P. Rozier R.M. Chiche J. Mondragón L. Riley J.S. et al.Parkin-independent mitophagy controls chemotherapeutic response in cancer cells.Cell Rep. 2017; 20: 2846-2859Abstract Full Text Full Text PDF PubMed Google Scholar; Yao et al., 2019Yao N. Wang C. Hu N. Li Y. Liu M. Lei Y. Chen M. Chen L. Chen C. Lan P. et al.Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog.Cell Death Dis. 2019; 10: 232Crossref PubMed Scopus (23) Google Scholar), supporting a pro-survival role of mitophagy in cancer cells in response to chemo/radiotherapy (Abdrakhmanov et al., 2019Abdrakhmanov A. Kulikov A.V. Luchkina E.A. Zhivotovsky B. Gogvadze V. Involvement of mitophagy in cisplatin-induced cell death regulation.Biol. Chem. 2019; 400: 161-170Crossref PubMed Scopus (9) Google Scholar). However, the mechanisms at play in this survival response may be complicated. Cancer cells are primed to undergo apoptosis because they more easily undergo mitochondrial permeabilization compared with normal cells. Indeed, this is the basis for the therapeutic window that allows many cancer therapies to work (Sarosiek et al., 2013Sarosiek K.A. Ni Chonghaile T. Letai A. Mitochondria: gatekeepers of response to chemotherapy.Trends Cell Biol. 2013; 23: 612-619Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Autophagic degradation of" @default.
• W3134787367 created "2021-03-15" @default.
• W3134787367 creator A5048235189 @default.
• W3134787367 creator A5078084826 @default.
• W3134787367 date "2021-04-01" @default.
• W3134787367 modified "2023-10-17" @default.
• W3134787367 title "Autophagy and organelle homeostasis in cancer" @default.
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