Inscrição na biblioteca: Guest
Portal Digital Begell Biblioteca digital da Begell eBooks Diários Referências e Anais Coleções de pesquisa
Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2.2

ISSN Imprimir: 0893-9675
ISSN On-line: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2020034969
pages 21-30

Autophagy-Induced Drug Resistance in Liver Cancer

Rahul Kumar Vempati
Cancer Biology Lab, Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam, India
Rama Rao Malla
Cancer Biology Lab, Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India


Autophagy is a self-destructive process that occurs in the cells during abnormal conditions like protein aggregation due to misfolding, nutrient deprivation, damage to vital cell organelles, pathogenic infections, and during cancer. Typically, autophagy plays a key role in the renovation of new cells by balancing the equilibrium between cell death and cell renewal. Dysregulation of autophagy has a profound effect on protein turnover, mitochondrial homeostasis, clearance of damaged organelles, and cellular metabolism, which lead to neurodegenerative, metabolic, and proliferative diseases. Despite its antitumorigenic role, autophagy can promote cell proliferation by enhancing chemotherapeutic resistance in liver cancer. In the present review, we provide a comprehensive overview and discussion on the role of autophagy in the drug-resistant mechanisms of liver cancer.


  1. Fang Y, Tan J, Zhang Q. Signaling pathways and mechanisms of hypoxia-induced autophagy in the animal cells. Cell Biol Int. 2015;39:891-98.

  2. Galati S, Boni C, Gerra MC, Lazzaretti M, Buschini A. Autophagy: A player in response to oxidative stress and DNA damage. Oxidat Med Cell Longev. 2019;2019:5692958.

  3. Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. J Pathol. 2010;221:3-12.

  4. Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A. 2011;108:4788-93.

  5. Menzies FM, Moreau K, Rubinsztein DC. Protein misfolding disorders and macroautophagy. Curr Op Cell Biol. 2011;23:190-97.

  6. Wang K, Klionsky DJ. Mitochondria removal by autophagy. Autophagy. 2011;7:297-300.

  7. Rubinsztein DC, Shpilka T, Elazar Z. Mechanisms of autophagosome biogenesis. Curr Biol. 2012;22:R29-R34.

  8. Feng Y, He D, Yao Z, Klionsky DJ. The machinery of macroautophagy. Cell Res. 2014;24:24-41.

  9. Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nature Cell Biol. 2014;16:495-501.

  10. Li WW, Li J, Bao JK. Microautophagy: Lesser-known self-eating. Cell Mol Life Sci. 2012;69:1125-36.

  11. Dice JF. Chaperone-mediated autophagy. Autophagy. 2007;3:295-99.

  12. Liu L, Liao JZ, He XX, Li PY. The role of autophagy in hepatocellular carcinoma: Friend or foe. Oncotarget. 2017;8:57707-22.

  13. Lee YJ, Jang BK. The role of autophagy in hepatocellular carcinoma. Int J Mol Sci. 2015;16:26629-43.

  14. Yazdani HO, Huang H, Tsung A. Autophagy: Dual response in the development of hepatocellular carcinoma. Cells. 2019;8:91.

  15. Sheng J, Qin H, Zhang K, Li B, Zhang X. Targeting autophagy in chemotherapy-resistant of hepatocellular carcinoma. Am J Cancer Res. 2018;8:354-65.

  16. Cebollero E, Reggiori F. Regulation of autophagy in yeast Saccharomyces cerevisiae. Biochim Biophys Acta. 2009;1793:1413-21.

  17. Wen X, Klionsky DJ. An overview of macroautophagy in yeast. J Mol Biol. 2016;428:1681-99.

  18. Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y. A unified nomenclature for yeast autophagy-related genes. Develop Cell. 2003;5:539-45.

  19. Reggiori F, Klionsky DJ. Autophagic processes in yeast: Mechanism, machinery and regulation. Genetics. 2013;194:341-61.

  20. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. Dynamics and diversity in autophagy mechanisms: Lessons from yeast. Nat Rev Mol Cell Biol. 2009;10:458-67.

  21. Shibutani ST, Yoshimori T. A current perspective of autophagosome biogenesis. Cell Res. 2014;24:58-68.

  22. Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Op Cell Biol. 2010;22:132-39.

  23. Zachari M, Ganley IG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 2017; 61:585-96.

  24. 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.

  25. Mercer CA, Kaliappan A, Dennis PB. A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy. 2009;5:649-62.

  26. Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol. 2008;181:497-510.

  27. Kumar M, Papaleo E. A Pan-Cancer assessment of alterations of ULK1 kinase, an upstream regulator of autophagy. bioRxiv. 2019:702522.

  28. Burman C, Ktistakis NT. Regulation of autophagy by phosphatidylinositol 3-phosphate. FEBS Lett. 2010;584: 1302-12.

  29. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Diff. 2011;18:571-80.

  30. Jaber N, Zong WX. Class III PI3K Vps34: Essential roles in autophagy, endocytosis, and heart and liver function. Ann NY Acad Sci. 2013;1280:48-51.

  31. Proikas-Cezanne T, Takacs Z, Donnes P, Kohlbacher O. WIPI proteins: Essential PtdIns3P effectors at the nascent autophagosome. J Cell Sci. 2015;128:207-17.

  32. Mei Y, Su M, Sanishvili R, Chakravarthy S, Colbert CL, Sinha SC. Identification of BECN1 and ATG14 coiled-coil interface residues that are important for starvation-induced autophagy. Biochemistry. 2016;55:4239-53.

  33. Furuya N, Yu J, Byfield M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy. 2005;1:46-52.

  34. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A, Guan KL. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol. 2013;15:741-50.

  35. Chen Z, Li Y, Zhang C, Yi H, Wu C, Wang J, Liu Y, Tan J, Wen J. Downregulation of Beclin 1 and impairment of autophagy in a small population of colorectal cancer. Digest Dis Sci. 2013;58:2887-94.

  36. Jian M, Yunjia Z, Zhiying D, Yanduo J, Guocheng J. Interleukin 7 receptor activates PI3K/Akt/mTOR signaling pathway via downregulation of Beclin-1 in lung cancer. Mol Carcinogen. 2019;58:358-65.

  37. Zhou W, Yue C, Deng J, Hu R, Xu J, Feng L, Lan Q, Zhang W, Ji D, Wu J, Liu Q, Liu A. Autophagic protein Beclin 1 serves as an independent positive prognostic biomarker for non-small cell lung cancer. PLoS One. 2013;8:e80338.

  38. Huang X, Bai HM, Chen L, Li B, Lu YC. Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J Clin Neurosci. 2010;17:1515-19.

  39. Osawa T, Noda NN. Atg2: A novel phospholipid transfer protein that mediates de novo autophagosome biogenesis. Protein Sci. 2019;28:1005-12.

  40. Maeda S, Otomo C, Otomo T. The autophagic membrane tether ATG2A transfers lipids between membranes. eLife. 2019;8.

  41. Feng Y, Klionsky DJ. Autophagic membrane delivery through ATG9. Cell Res. 2017;27:161-62.

  42. Walczak M, Martens S. Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation. Autophagy. 2013;9:424-25.

  43. Nakatogawa H. Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy. Essays Biochem. 2013;55:39-50.

  44. Matsushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y, Inagaki F. Structure of Atg5.Atg16, a complex essential for autophagy. J Bio Chem. 2007;282:6763-72.

  45. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell. 2008;19:2092-100.

  46. Thukral L, Sengupta D, Ramkumar A, Murthy D, Agrawal N, Gokhale RS. The molecular mechanism underlying recruitment and insertion of lipid-anchored LC3 protein into membranes. Biophys J. 2015;109:2067-78.

  47. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, 0vervatn A, Bjerkay G, Johansen T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Bio Chem. 2007;282:24131-45.

  48. Pankiv S, Alemu EA, Brech A, Bruun JA, Lamark T, Overvatn A, Bjerkey G, Johansen T. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate micro-tubule plus end-directed vesicle transport. J Cell Biol. 2010;188:253-69.

  49. Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L, Calafat J, Janssen H, Wubbolts R, Neefjes J. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol. 2001;11:1680-85.

  50. Sir D, Tian Y, Chen WL, Ann DK, Yen TS, Ou JH. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci U S A. 2010;107:4383-88.

  51. Tian Y, Sir D, Kuo CF, Ann DK, Ou JH. Autophagy required for hepatitis B virus replication in transgenic mice. J Virol. 2011;85:13453-56.

  52. Tang H, Da L, Mao Y, Li Y, Li D, Xu Z, Li F, Wang Y, Tiollais P, Li T, Zhao M. Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology (Baltimore, MD). 2009;49:60-71.

  53. Sir D, Chen WL, Choi J, Wakita T, Yen TS, Ou JH. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology (Baltimore, MD). 2008;48:1054-61.

  54. Wang L, Tian Y, Ou JH. HCV induces the expression of Rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS Path. 2015;11:e1004764.

  55. Estrabaud E, De Muynck S, Asselah T. Activation of unfolded protein response and autophagy during HCV infection modulates innate immune response. J Hepatol. 2011;55:1150-53.

  56. Mohl BP, Tedbury PR, Griffin S, Harris M. Hepatitis C virus-induced autophagy is independent of the unfolded protein response. J Virol. 2012;86:10724-32.

  57. Korenaga M, Wang T, Li Y, Showalter LA, Chan T, Sun J, Weinman SA. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Bio Chem. 2005;280:37481-88.

  58. Ivanov AV, Smirnova OA, Ivanova ON, Masalova OV, Kochetkov SN, Isaguliants MG. Hepatitis C virus proteins activate NRF2/ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells. PLoS One. 20ll;6:e24957.

  59. Carvajal-Yepes M, Himmelsbach K, Schaedler S, Ploen D, Krause J, Ludwig L, Weiss T, Klingel K, Hildt E. Hepatitis C virus impairs the induction of cytoprotective Nrf2 target genes by delocalization of small Maf proteins. J Bio Chem. 20ll;286:8941-51.

  60. Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism. World J Gastroenterol. 20l4;20:l7756-72.

  61. Ran M, Chen H, Liang B, Liao W, Jiang J, Huang J, Ning C, Zang N, Zhou B, Liao Y, Liu H, Qin F, Yang Q, Li J, Ho W, Liang H, Ye L. Alcohol-induced autophagy via up-regulation of PIASy promotes HCV replication in human hepatoma cells. Cell Death Dis. 20l8;9:898.

  62. Dhamija E, Paul SB, Kedia S. Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: An in-creasing concern. Indian J Med Res. 20l9;l49:9-l7.

  63. Zhang Z, Yao Z, Chen Y, Qian L, Jiang S, Zhou J, Shao J, Chen A, Zhang F, Zheng S. Lipophagy and liver disease: New perspectives to better understanding and therapy. Biomed Pharmacother. 20l8;97:339-48.

  64. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B. Promotion of tumorigenesis by heterozygous disruption of the beclin l autophagy gene. J Clin Investig. 2003;ll2:l809-20.

  65. Kang KF, Wang XW, Chen XW, Kang ZJ, Zhang X, Wilbur RR, Cheng F, Zhou SF. Beclin l and nuclear factor-KBp65 are upregulated in hepatocellular carcinoma. Oncol Lett. 20l3;5:l8l3-l8.

  66. Liang C, Li W, Ge H, Zhang K, Li G, Wu J. Role of Beclinl expression in patients with hepatocellular carcinoma: A meta-analysis. OncoTargets Ther. 20l8;ll: 2387-97.

  67. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N. Autophagy-deficient mice develop multiple liver tumors. Gene Develop. 20ll;25:795-800.

  68. Islam MA, Sooro MA, Zhang P. Autophagic regulation of p62 is critical for cancer therapy. Int J Mol Sci. 20l8;l9.

  69. Xing M, Li P, Wang X, Li J, Shi J, Qin J, Zhang X, Ma Y, Francia G, Zhang JY. Overexpression of p62/IMP2 can promote cell migration in hepatocellular carcinoma via activation of the Wnt/p-catenin pathway. Cancers. 2019;12.

  70. Zhang H, Zhang Y, Zhu X, Chen C, Zhang C, Xia Y, Zhao Y, Andrisani O, Kong L. DEAD box protein 5 inhibits liver tumorigenesis by stimulating autophagy via interaction with p62/SQSTMl. Hepatology (Baltimore, MD). 2019;69:1046-63.

  71. Huang F, Wang BR, Wang YG. Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma. World J Gastroenterol. 2018;24:4643-51.

  72. Song YJ, Zhang SS, Guo XL, Sun K, Han ZP, Li R, Zhao QD, Deng WJ, Xie XQ, Zhang JW, Wu MC, Wei LX. Autophagy contributes to the survival of CDl33+ liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment. Cancer Lett. 20l3;339:70-81.

  73. Ciccarone F, Castelli S, Ciriolo MR. Oxidative stress-driven autophagy acROSs onset and therapeutic outcome in hepatocellular carcinoma. Oxidat Med Cell Longev. 20l9;20l9:6050l23.

  74. Ding ZB, Hui B, Shi YH, Zhou J, Peng YF, Gu CY, Yang H, Shi GM, Ke AW, Wang XY, Song K, Dai Z, Shen YH, Fan J. Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. Clin Cancer Res. 2011;17:6229-38.

  75. Zhang Z, Rong L, Li YP. Flaviviridae viruses and oxidative stress: implications for viral pathogenesis. Oxidat Med Cell Longev. 20l9;20l9:l409582.

  76. Yuan X, Wang B, Yang L, Zhang Y. The role of ROS-induced autophagy in hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 20l8;42:306-l2.

  77. Fu XT, Shi YH, Zhou J, Peng YF, Liu WR, Shi GM, Gao Q, Wang XY, Song K, Fan J, Ding ZB. MicroRNA-30a suppresses autophagy-mediated anoikis resistance and metastasis in hepatocellular carcinoma. Cancer Lett. 20l8;4l2:l08-l7.

  78. Ren WW, Li DD, Chen X, Li XL, He YP, Guo LH, Liu LN, Sun LP, Zhang XP. MicroRNA-l25b reverses oxal- iplatin resistance in hepatocellular carcinoma by negatively regulating EVAlA mediated autophagy. Cell Death Dis. 20l8;9:547.

  79. Stiuso P, Potenza N, Lombardi A, Ferrandino I, Monaco A, Zappavigna S, Vanacore D, Mosca N, Castiello F, Porto S, Addeo R, Prete SD, De Vita F, Russo A, Caraglia M. MicroRNA-423-5p promotes autophagy in cancer cells and is increased in serum from hepatocarcinoma patients treated with sorafenib. Mol Ther Nucl Acids. 2015;4:e233.

  80. Chang Y, Yan W, He X, Zhang L, Li C, Huang H, Nace G, Geller DA, Lin J, Tsung A. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology. 20l2;l43:l77-87.e8.

  81. Yang J, He Y, Zhai N, Ding S, Li J, Peng Z. MicroR-NA-l8la inhibits autophagy by targeting Atg5 in hepato-cellular carcinoma. Frontiers Biosci (Landmark edition). 20l8;23:388-96.

  82. Jin F, Wang Y, Li M, Zhu Y, Liang H, Wang C, Wang F, Zhang CY, Zen K, Li L. MiR-26 enhances chemosensitivity and promotes apoptosis of hepatocellular carcinoma cells through inhibiting autophagy. Cell Death Dis. 20l7;8:e2540.

  83. Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, Coppes RP, Engedal N, Mari M, Reggiori F. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14:1435-55.

  84. Zhang N, Xie H, Lu W, Li F, Li J, Guo Z. Chloroquine sensitizes hepatocellular carcinoma cells to chemotherapy via blocking autophagy and promoting mitochondrial dysfunction. Int J Clin Exper Pathol. 2017;10:10056-65.

  85. Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, Hosui A, Ishida H, Tatsumi T, Kanto T, Hiramatsu N, Fujita N, Yoshimori T, Hayashi N. Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int J Cancer. 2012;131:548-57.

  86. Lu S, Yao Y, Xu G, Zhou C, Zhang Y, Sun J, Jiang R, Shao Q, Chen Y. CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis. 2018;9:646.

  87. Wang S, Wang Y, Xun X, Zhang C, Xiang X, Cheng Q, Hu S, Li Z, Zhu J. Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids. J Exper Clin Cancer Res. 2020;39:22.

  88. Witt-Kehati D, Fridkin A, Alaluf MB, Zemel R, Shlomai A. Inhibition of pMAPK14 overcomes resistance to sorafenib in hepatoma cells with hepatitis b virus. Trans Oncol. 2018;11:511-17.

  89. Su YC, Davuluri GV, Chen CH, Shiau DC, Chen CC, Chen CL, Lin YS, Chang CP. Galectin-1-induced autophagy facilitates cisplatin resistance of hepatocellular carcinoma. PLoS One. 2016;11:e0148408.

  90. Fu XT, Song K, Zhou J, Shi YH, Liu WR, Shi GM, Gao Q, Wang XY, Ding ZB, Fan J. Tumor-associated macrophages modulate resistance to oxaliplatin via inducing autophagy in hepatocellular carcinoma. Cancer Cell Int. 2019;19:71.

Articles with similar content:

Driving Cytotoxic Natural Killer Cells into Melanoma: If CCL5 Plays the Music, Autophagy Calls the Shots
Critical Reviews™ in Oncogenesis, Vol.23, 2018, issue 5-6
Muhammad Zaeem Noman, Markus Ollert, Ludovic Menard, Malina Xiao, Bassam Janji, Martyna Szpakowska, Andy Chevigne, Guy Berchem, Manon Bosseler
Interleukin-33 and its Receptor in Pulmonary Inflammatory Diseases
Critical Reviews™ in Immunology, Vol.35, 2015, issue 6
Jing Zhao, Yutong Zhao
Sirtuins in Brain Aging and Neurological Disorders
Critical Reviews™ in Eukaryotic Gene Expression, Vol.27, 2017, issue 4
Muhammad Imran Qadir, Sidra Anwar
Interfering with Nuclear Transport as a Means of Interrupting Transcription Factor Activity in Cancer
Critical Reviews™ in Eukaryotic Gene Expression, Vol.29, 2019, issue 5
Pauline J. van der Watt, Aderonke F. Ajayi-Smith, Virna D. Leaner
Role of p53 in Systemic Autoimmune Diseases
Critical Reviews™ in Immunology, Vol.34, 2014, issue 6
Hirotoshi Kawashima, Hiroshi Nakajima, Hiroaki Takatori, Kotaro Suzuki