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Autophagy: Therapeutic Approach For Cancer Treatment
Abstract
Intracellular catabolic degradation of lysosomal components is called as autophagy. The autophagy is working for “Cellular Garbage Disposal and Intracellular Recycling”. It serves to orchestrate the process of cellular homeostasis. It is achieved through elimination of superfluous or damaged proteins and organelles; through invading microbes; through the provision of substrates for energy generation and through the biosynthesis in stress. The autophagy promotes the cellular health and there by the health of body of animal. The autophagy is critical for development, differentiation and maintenance of working of the cell. It also play key role in the host defense against pathogens. The cancer is a complex process. In cancer cell, the autophagy exerts its influence in multiple ways. The role of autophagy in cancer is context dependent. Chronic tissue damage and cell death can lead to the initiation of cancer. In cancer cell, the autophagy is working as a cytoprotective survival pathway. The autophagy prevents chronic tissue damage and cell death. With this reference, the stimulation or restoration of autophagy may prevent cancer. In practical sense, the cancer cells deserve capability of utilization of autophagy for enhancement of their fitness and ability of survival with altered metabolism. In this reference, strategy of inhibition of autophagy is the need for treatment for cancer.
Keywords
References
Kobayashi S (2015). "Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy". Biological & Pharmaceutical Bulletin. 38 (8): 1098–103. doi:10.1248/bpb.b15-00096. PMID 26235572.
Mizushima N, Komatsu M (November 2011). "Autophagy: renovation of cells and tissues". Cell. 147 (4): 728–41. doi:10.1016/j.cell.2011.10.026. PMID 22078875.
Xie Z, Klionsky DJ (October 2007). "Autophagosome formation: core machinery and adaptations". Nature Cell Biology. 9 (10): 1102–9. doi:10.1038/ncb1007-1102. PMID 17909521.
Mizushima N, Yoshimori T, Ohsumi Y (10 November 2011). "The role of Atg proteins in autophagosome formation". Annual Review of Cell and Developmental Biology. 27 (1): 107–32. doi:10.1146/annurev-cellbio-092910-154005. PMID 21801009.
Klionsky DJ (August 2008). "Autophagy revisited: a conversation with Christian de Duve". Autophagy. 4 (6): 740–3. doi:10.4161/auto.6398. PMID 18567941.
Harding TM, Morano KA, Scott SV, Klionsky DJ (November 1995). "Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway". The Journal of Cell Biology. 131 (3): 591–602. doi:10.1083/jcb.131.3.591. PMC 2120622. PMID 7593182.
Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541.
Ashford TP, Porter KR (January 1962). "Cytoplasmic components in hepatic cell lysosomes". The Journal of Cell Biology. 12 (1): 198–202. doi:10.1083/jcb.12.1.198. PMC 2106008. PMID 13862833.
Hruban Z, Spargo B, Swift H., Wissler RW, Kleinfeld RG (June 1963). "Focal cytoplasmic degradation". The American Journal of Pathology. 42 (6): 657–83. PMC 1949709. PMID 13955261.
Deter RL, Baudhuin P, De Duve C (November 1967). "Participation of lysosomes in cellular autophagy induced in rat liver by glucagon". The Journal of Cell Biology. 35 (2): C11–6. doi:10.1083/jcb.35.2.c11. PMC 2107130. PMID 6055998.
Dunn WA, Schroder LA, Aris JP (2013). "Historical overview of autophagy". In Wang H (ed.). Autophagy and Cancer. Springer. pp. 3–4. ISBN 9781461465614.
Thumm M, Egner R, Koch B, Schlumpberger M, Straub M, Veenhuis M, Wolf DH (August 1994). "Isolation of autophagocytosis mutants of Saccharomyces cerevisiae". FEBS Letters. 349 (2): 275–80. doi:10.1016/0014-5793(94)00672-5. PMID 8050581.
Klionsky DJ, Cueva R, Yaver DS (October 1992). "Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway". The Journal of Cell Biology. 119 (2): 287–99. doi:10.1083/jcb.119.2.287. PMC 2289658. PMID 1400574.
Klionsky DJ, Cregg JM, Dunn WA, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y (October 2003). "A unified nomenclature for yeast autophagy-related genes". Developmental Cell. 5 (4): 539–45. doi:10.1016/s1534-5807(03)00296-x. PMID 14536056.
Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (December 1999). "Induction of autophagy and inhibition of tumorigenesis by beclin 1". Nature. 402 (6762): 672–6. doi:10.1038/45257. PMID 10604474.
Van Noorden R, Ledford H (October 2016). "Medicine Nobel for research on how cells 'eat themselves'". Nature. 538 (7623): 18–19. doi:10.1038/nature.2016.20721. PMID 27708326.
Mercer CA, Kaliappan A, Dennis PB.. Macroautophagy-dependent, intralysosomal cleavage of a betaine homocysteine methyltransferase fusion protein requires stable multimerization. Autophagy 2008; 4:185–94; PMID:18059170; http://dx.doi.org/10.4161/auto.5275 [PubMed] [CrossRef] [Google Scholar]
Mizushima N, Ohsumi Y, Yoshimori T (December 2002). "Autophagosome formation in mammalian cells". Cell Structure and Function. 27 (6): 421–9. doi:10.1247/csf.27.421. PMID 12576635.
Youle RJ, Narendra DP (January 2011). "Mechanisms of mitophagy". Nature Reviews. Molecular Cell Biology. 12 (1): 9–14. doi:10.1038/nrm3028. PMC 4780047. PMID 21179058.
Lee J, Giordano S, Zhang J (January 2012). "Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling". The Biochemical Journal. 441 (2): 523–40. doi:10.1042/BJ20111451. PMC 3258656. PMID 22187934.
Ding WX, Yin XM (July 2012). "Mitophagy: mechanisms, pathophysiological roles, and analysis". Biological Chemistry. 393 (7): 547–64. doi:10.1515/hsz-2012-0119. PMC 3630798. PMID 22944659.
Till A, Lakhani R, Burnett SF, Subramani S (2012). "Pexophagy: the selective degradation of peroxisomes". International Journal of Cell Biology. 2012: 512721. doi:10.1155/2012/512721. PMC 3320016. PMID 22536249.
Liu K, Czaja MJ (January 2013). "Regulation of lipid stores and metabolism by lipophagy". Cell Death and Differentiation. 20 (1): 3–11. doi:10.1038/cdd.2012.63. PMC 3524634. PMID 22595754.
Lei L (March 2017). "Chlorophagy: Preventing sunburn". Nature Plants. 3 (3): 17026. doi:10.1038/nplants.2017.26. PMID 28248315.
An H, Harper JW (February 2018). "Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy". Nature Cell Biology. 20 (2): 135–143. doi:10.1038/s41556-017-0007-x. PMC 5786475. PMID 29230017.
Levine B, Mizushima N, Virgin HW (January 2011). "Autophagy in immunity and inflammation". Nature. 469 (7330): 323–35. doi:10.1038/nature09782. PMC 3131688. PMID 21248839.
Česen MH, Pegan K, Spes A, Turk B (July 2012). "Lysosomal pathways to cell death and their therapeutic applications". Experimental Cell Research. 318 (11): 1245–51. doi:10.1016/j.yexcr.2012.03.005. PMID 22465226.
Homma, K.S. (2011). "List of autophagy-related proteins and 3D structures". Autophagy Database. 290. Archived from the original on 2012-08-01. Retrieved 2012-10-08
Castro-Obregon, Susana (2010). "The Discovery of Lysosomes and Autophagy". Nature Education. 3 (9): 49.
Bandyopadhyay U, Kaushik S, Varticovski L, Cuervo AM (September 2008). "The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane". Molecular and Cellular Biology. 28 (18): 5747–63. doi:10.1128/MCB.02070-07. PMC 2546938. PMID 18644871.
Ward C, Martinez-Lopez N, Otten EG, Carroll B, Maetzel D, Singh R, Sarkar S, Korolchuk VI (April 2016). "Autophagy, lipophagy and lysosomal lipid storage disorders". Biochimica et Biophysica Acta. 1861 (4): 269–84. doi:10.1016/j.bbalip.2016.01.006. PMID 26778751.
Elander PH, Minina EA, Bozhkov PV (March 2018). "Autophagy in turnover of lipid stores: trans-kingdom comparison". Journal of Experimental Botany. 69 (6): 1301–1311. doi:10.1093/jxb/erx433. PMID 29309625.
Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, et al. Autophagy regulates lipid metabolism. Nature 2009;458:1131–5.
van Zutphen T, Todde V, de Boer R, Kreim M, Hofbauer HF, Wolinski H, Veenhuis M, van der Klei IJ, Kohlwein SD (January 2014). "Lipid droplet autophagy in the yeast Saccharomyces cerevisiae". Molecular Biology of the Cell. 25 (2): 290–301. doi:10.1091/mbc.E13-08-0448. PMC 3890349. PMID 24258026.
Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 2010;141:290–303.
Li Y, Wang Y, Kim E, Beemiller P, Wang CY, Swanson J, et al. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J Biol Chem 2007;282: 35803–13.
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 2007;9:218–24.
Sakaki K, Wu J, Kaufman RJ. Protein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulum. J Biol Chem 2008;283:15370–80.
Neufeld TP. TOR-dependent control of autophagy: biting the hand that feeds. Curr Opin Cell Biol 2010;22:157–68.
Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010;22:124–31.
Rabinowitz JD, White E. Autophagy and metabolism. Science 2010;330:1344–8.
Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol 2010;22:177–80.
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13:132–41.
Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 2011; 331:456–61.
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214–26.
Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010;141:1146–58.
Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, et al. Autophagy mediate pharmacological lifespan extension by spermidine and resveratrol. Aging 2009;1:961–70.
Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther 2010;9:1092–9.
Renna M, Jimenez-Sanchez M, Sarkar S, Rubinsztein DC. Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. J Biol Chem 2010;285:11061–7.
Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy. Nat Rev Drug Discov 2007;6:304–12.
Oku M, Sakai Y. Peroxisomes as dynamic organelles: autophagic degradation. FEBS J 2010;277:3289–94.
Davis LI, Blobel G (1986). "Identification and characterization of a nuclear pore complex protein". Cell. 45 (5): 699–709. doi:10.1016/0092-8674(86)90784-1. PMID 3518946.
Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 2007;131:1149–63.
Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 2007;282:24131–45.
Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL, Bruun JA, et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell 2009;33:505–16.
Wild P, Dikic I. Mitochondria get a Parkin’ ticket. Nat Cell Biol 2010;12:104–6.
Zhang J, Ney PA. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 2009;16:939–46.
Schwarten M, Mohrluder J, Ma P, Stoldt M, Thielmann Y, Stangler T, et al. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy 2009;5:690–8.
Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 2010;11:45–51.
Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, Dorsey FC, et al. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci U S A 2007;104:19500–5.
Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, Chen M, et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 2008;454:232–5.
Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 2005;169:425–34.
Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, SuzukiMigishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006;441:885–9.
Zatloukal K, French SW, Stumptner C, Strnad P, Harada M, Toivola DM, et al. From Mallory to Mallory-Denk bodies: what, how and why? Exp Cell Res 2007;313:2033–49.
Perlmutter DH. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ 2009;16:39–45.
Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010; 329:229–32.
Wu JJ, Quijano C, Chen E, Liu H, Cao L, Fergusson MM, et al. Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging 2009;1:425–37.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009;137: 1062–75.
Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, et al. Autophagy is required to maintain muscle mass. Cell Metab 2009;10:507–15.
Manjithaya R, Nazarko TY, Farre JC, Subramani S. Molecular mechanism and physiological role of pexophagy. FEBS Lett 2010;584:1367–73.
Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 2005;171:603–14.
Moscat J, Diaz-Meco MT, Wooten MW. Signal integration and diversification through the p62 scaffold protein. Trends Biochem Sci 2007;32:95–100.
Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, et al. The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell 2008;13:343–54.
Maeda S, Kamata H, Luo JL, Leffert H, Karin M. I K K beta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005;121:977–90.
Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 2010;12:213–23.
Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, et al. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 2010;30:3275–85.
Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA, Overvatn A, et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop byinducing antioxidant response element-driven gene transcription. J Biol Chem 2010;285: 22576–91.
Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579–91.
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 2010;52:774–88.
Jung HS, Chung KW, Won Kim J, Kim J, Komatsu M, Tanaka K, et al. Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab 2008;8: 318–24.
Ebato C, Uchida T, Arakawa M, Komatsu M, Ueno T, Komiya K, et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab 2008; 8:325–32.
Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 2010; 11:467–78.
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132: 27–42.
Sass M and Kovács J. (1975). Ecdysterone and an analogue of juvenile hormone on the autophagy in the cells of fat body of Mamestra brassicae. Acta Biol Acad Sci Hung. 1975; 26(3-4):189-96. PMID: 1234402
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444:337–42.
Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392–5.
Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature 2004; 432:1032–6.
Kuma A, Mizushima N. Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin Cell Dev Biol 2010; 21:683–90.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029–33.
Galluzzi L, Kepp O, Zitvogel L, Kroemer G. Bacterial invasion: linking autophagy and innate immunity. Curr Biol 2010; 20: R106–8.
Netea MG, Joosten LA. A NOD for autophagy. Nat Med 2010; 16:28–30.
Danese S, Mantovani A. Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene 2010;29: 3313–23.
Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 2010; 16:90–7.
Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 2010; 11: 55–62.
Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, et al. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 2010; 141:1135–45.
Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007; 21 :1367–81.
Young AR, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JF, et al. Autophagy mediates the mitotic senescence transition. Genes Dev 2009; 23: 798–803.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64.
Blagosklonny MV. Prevention of cancer by inhibiting aging. Cancer Biol Ther 2008;7: 1520–4.
Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 2011; 25: 460–70.
Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell 2010; 22:165–78.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011; 25: 717–29.
DOI: https://doi.org/10.37591/jomcct.v10i3.2486
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