Inhibition of autophagy in hepatocarcinoma cells promotes chemotherapeutic agent-induced apoptosis during nutrient deprivation

Guo,Xian-Ling; Hu,Fei; Wang,Hui; Fang,Jue-Min; Zhu,Zhong-Ζheng; Wei,Li-Χin; Xu,Qing

doi:10.3892/or.2017.6115

Inhibition of autophagy in hepatocarcinoma cells promotes chemotherapeutic agent-induced apoptosis during nutrient deprivation

Authors:
- Xian-Ling Guo
- Fei Hu
- Hui Wang
- Jue-Min Fang
- Zhong-Ζheng Zhu
- Li-Χin Wei
- Qing Xu
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Affiliations: Department of Medical Oncology, Dermatology Hospital, Tongji University, Shanghai 200072, P.R. China, Department of Medical Oncology, 10th People's Hospital, Tongji University, Shanghai 200072, P.R. China, Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, P.R. China
Published online on: November 27, 2017 https://doi.org/10.3892/or.2017.6115
Pages: 773-783

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Abstract

Autophagy is a lysosome-dependent process involved in protein and organelle degradation. It has been suggested that autophagy is activated in nutrient-deficient condition and plays an important role in protecting cells from nutrient shortage. However, the effect of autophagy on chemotherapy during nutrient deficiency has been rarely researched. In the present study, we discovered that hepatocarcinoma cells exhibit chemoinsensitivity accompanied by the activation of autophagy when cultured in nutrient-deprived medium. Inhibition of autophagy by 3-methyladenine or siRNA‑targeted Beclin 1 increased the nutrient deprivation‑induced apoptosis and chemosensitivity in hepatocarcinoma cells. Furthermore, decreased mitochondrial mass was detected when cells underwent autophagy. The present study suggests that induction of autophagy confers a survival advantage for hepatocarcinoma cells during nutrient deprivation, not only rescuing cells from nutrient deficiency-induced cell apoptosis, but also protecting cells from chemotherapy-induced cell death. Combined usage of the inhibition of autophagy and conventional chemotherapeutic agents could be an effective therapy for hepatocarcinoma during nutrient deprivation.

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1	Tang ZY: Hepatocellular carcinoma - cause, treatment and metastasis. World J Gastroenterol. 7:445–454. 2001. View Article : Google Scholar : PubMed/NCBI
2	Bartlett A and Heaton N: Hepatocellular carcinoma: Defining the place of surgery in an era of organ shortage. World J Gastroenterol. 14:4445–4453. 2008. View Article : Google Scholar : PubMed/NCBI
3	Abedin MJ, Wang D, McDonnell MA, Lehmann U and Kelekar A: Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ. 14:500–510. 2007. View Article : Google Scholar : PubMed/NCBI
4	Katayama M, Kawaguchi T, Berger MS and Pieper RO: DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells. Cell Death Differ. 14:548–558. 2007. View Article : Google Scholar : PubMed/NCBI
5	Kaushal GP, Kaushal V, Herzog C and Yang C: Autophagy delays apoptosis in renal tubular epithelial cells in cisplatin cytotoxicity. Autophagy. 4:710–712. 2008. View Article : Google Scholar : PubMed/NCBI
6	Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A and Thompson CB: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 117:326–336. 2007. View Article : Google Scholar : PubMed/NCBI
7	Maiuri MC, Zalckvar E, Kimchi A and Kroemer G: Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 8:741–752. 2007. View Article : Google Scholar : PubMed/NCBI
8	Levine B and Yuan J: Autophagy in cell death: An innocent convict? J Clin Invest. 115:2679–2688. 2005. View Article : Google Scholar : PubMed/NCBI
9	Ogier-Denis E and Codogno P: Autophagy: A barrier or an adaptive response to cancer. Biochim Biophys Acta. 1603:113–128. 2003.PubMed/NCBI
10	Qian J, Feng GS and Vogl T: Combined interventional therapies of hepatocellular carcinoma. World J Gastroenterol. 9:1885–1891. 2003. View Article : Google Scholar : PubMed/NCBI
11	Levine B and Klionsky DJ: Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev Cell. 6:463–477. 2004. View Article : Google Scholar : PubMed/NCBI
12	Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI
13	Kondo Y, Kanzawa T, Sawaya R and Kondo S: The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 5:726–734. 2005. View Article : Google Scholar : PubMed/NCBI
14	Kroemer G and Jäättelä M: Lysosomes and autophagy in cell death control. Nat Rev Cancer. 5:886–897. 2005. View Article : Google Scholar : PubMed/NCBI
15	Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, Baba M, Baehrecke EH, Bahr BA, Ballabio A, et al: Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 4:151–175. 2008. View Article : Google Scholar : PubMed/NCBI
16	Yu SW, Baek SH, Brennan RT, Bradley CJ, Park SK, Lee YS, Jun EJ, Lookingland KJ, Kim EK, Lee H, et al: Autophagic death of adult hippocampal neural stem cells following insulin withdrawal. Stem Cells. 26:2602–2610. 2008. View Article : Google Scholar : PubMed/NCBI
17	Gozuacik D and Kimchi A: Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 23:2891–2906. 2004. View Article : Google Scholar : PubMed/NCBI
18	Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y, Ueno T, Ochiai A and Esumi H: Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 67:9677–9684. 2007. View Article : Google Scholar : PubMed/NCBI
19	De Flora S, Scarfì S, Izzotti A, D'Agostini F, Chang CC, Bagnasco M, De Flora A and Trosko JE: Induction by 7,12-dimethylbenz(a)anthracene of molecular and biochemical alterations in transformed human mammary epithelial stem cells, and protection by N-acetylcysteine. Int J Oncol. 29:521–529. 2006.PubMed/NCBI
20	Tanida I, Minematsu-Ikeguchi N, Ueno T and Kominami E: Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy. 1:84–91. 2005. View Article : Google Scholar : PubMed/NCBI
21	Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, Packer M, Schneider MD and Levine B: Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 122:927–939. 2005. View Article : Google Scholar : PubMed/NCBI
22	Cao Y and Klionsky DJ: Physiological functions of Atg6/Beclin 1: A unique autophagy-related protein. Cell Res. 17:839–849. 2007. View Article : Google Scholar : PubMed/NCBI
23	Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier-Hayes L, Fitzgerald P, Guio-Carrion A, Waterhouse NJ, Li CW, et al: GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell. 129:983–997. 2007. View Article : Google Scholar : PubMed/NCBI
24	Ravikumar B, Berger Z, Vacher C, O'Kane CJ and Rubinsztein DC: Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet. 15:1209–1216. 2006. View Article : Google Scholar : PubMed/NCBI
25	Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ and Semenza GL: Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 283:10892–10903. 2008. View Article : Google Scholar : PubMed/NCBI
26	Amaravadi RK and Thompson CB: The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res. 13:7271–7279. 2009. View Article : Google Scholar
27	Bauvy C, Gane P, Arico S, Codogno P and Ogier-Denis E: Autophagy delays sulindac sulfide-induced apoptosis in the human intestinal colon cancer cell line HT-29. Exp Cell Res. 268:139–149. 2001. View Article : Google Scholar : PubMed/NCBI
28	Viola G, Bortolozzi R, Hamel E, Moro S, Brun P, Castagliuolo I, Ferlin MG and Basso G: MG-2477, a new tubulin inhibitor, induces autophagy through inhibition of the Akt/mTOR pathway and delayed apoptosis in A549 cells. Biochem Pharmacol. 83:16–26. 2012. View Article : Google Scholar : PubMed/NCBI
29	Liao A, Hu R, Zhao Q, Li J, Li Y, Yao K, Zhang R, Wang H, Yang W and Liu Z: Autophagy induced by FTY720 promotes apoptosis in U266 cells. Eur J Pharm Sci. 45:600–605. 2012. View Article : Google Scholar : PubMed/NCBI
30	Zhang YH, Wu YL, Tashiro S, Onodera S and Ikejima T: Reactive oxygen species contribute to oridonin-induced apoptosis and autophagy in human cervical carcinoma HeLa cells. Acta Pharmacol Sin. 32:1266–1275. 2011. View Article : Google Scholar : PubMed/NCBI
31	Fujii S, Mitsunaga S, Yamazaki M, Hasebe T, Ishii G, Kojima M, Kinoshita T, Ueno T, Esumi H and Ochiai A: Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome. Cancer Sci. 99:1813–1819. 2008.PubMed/NCBI
32	Ogata A, Yanagie H, Ishikawa E, Morishita Y, Mitsui S, Yamashita A, Hasumi K, Takamoto S, Yamase T and Eriguchi M: Antitumour effect of polyoxomolybdates: Induction of apoptotic cell death and autophagy in in vitro and in vivo models. Br J Cancer. 98:399–409. 2008. View Article : Google Scholar : PubMed/NCBI
33	Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L and Elazar Z: Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26:1749–1760. 2007. View Article : Google Scholar : PubMed/NCBI
34	Chen Y, Azad MB and Gibson SB: Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ. 16:1040–1052. 2009. View Article : Google Scholar : PubMed/NCBI
35	Bensaad K, Cheung EC and Vousden KH: Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J. 28:3015–3026. 2009. View Article : Google Scholar : PubMed/NCBI
36	Bruno P, Calastretti A, Priulla M, Asnaghi L, Scarlatti F, Nicolin A and Canti G: Cell survival under nutrient stress is dependent on metabolic conditions regulated by Akt and not by autophagic vacuoles. Cell Signal. 19:2118–2126. 2007. View Article : Google Scholar : PubMed/NCBI