Resveratrol enhances cisplatin-induced apoptosis in human hepatoma cells via glutamine metabolism inhibition
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초록
Cisplatin is one of the most effective chemotherapeutic drugs used in the treatment of HCC, but many patients will ultimately relapse with cisplatin-resistant disease. Used in combination with cisplatin, resveratrol has synergistic effect of increasing chemosensitivity of cisplatin in various cancer cells. However, the mechanisms of resveratrol enhancing cisplatininduced toxicity have not been well characterized. Our study showed that resveratrol enhances cisplatin toxicity in human hepatoma cells via an apoptosis-dependent mechanism. Further studies reveal that resveratrol decreases the absorption of glutamine and glutathione content by reducing the expression of glutamine transporter ASCT2. Flow cytometric analyses demonstrate that resveratrol and cisplatin combined treatment leads to a significant increase in ROS production compared to resveratrol or cisplatin treated hepatoma cells alone. Phosphorylated H2AX (H2AX) foci assay demonstrate that both resveratrol and cisplatin treatment result in a significant increase of H2AX foci in hepatoma cells, and the resveratrol and cisplatin combined treatment results in much more H2AX foci formation than either resveratrol or cisplatin treatment alone. Furthermore, our studies show that over-expression of ASCT2 can attenuate cisplatin-induced ROS production, H2AX foci formation and apoptosis in human hepatoma cells. Collectively, our studies suggest resveratrol may sensitize human hepatoma cells to cisplatin chemotherapy via glutamine metabolism inhibition.
Abstract
Cisplatin is one of the most effective chemotherapeutic drugs used in the treatment of HCC, but many patients will ultimately relapse with cisplatin-resistant disease. Used in combination with cisplatin, resveratrol has synergistic effect of increasing chemosensitivity of cisplatin in various cancer cells. However, the mechanisms of resveratrol enhancing cisplatininduced toxicity have not been well characterized. Our study showed that resveratrol enhances cisplatin toxicity in human hepatoma cells via an apoptosis-dependent mechanism. Further studies reveal that resveratrol decreases the absorption of glutamine and glutathione content by reducing the expression of glutamine transporter ASCT2. Flow cytometric analyses demonstrate that resveratrol and cisplatin combined treatment leads to a significant increase in ROS production compared to resveratrol or cisplatin treated hepatoma cells alone. Phosphorylated H2AX (H2AX) foci assay demonstrate that both resveratrol and cisplatin treatment result in a significant increase of H2AX foci in hepatoma cells, and the resveratrol and cisplatin combined treatment results in much more H2AX foci formation than either resveratrol or cisplatin treatment alone. Furthermore, our studies show that over-expression of ASCT2 can attenuate cisplatin-induced ROS production, H2AX foci formation and apoptosis in human hepatoma cells. Collectively, our studies suggest resveratrol may sensitize human hepatoma cells to cisplatin chemotherapy via glutamine metabolism inhibition.
참고문헌 (36)
- Llovet JM, "Treatment of hepatocellular carcinoma", Curr Treat Options Gastroenterol, 7, pp.431~441 (2004)[DOI]
- Llovet JM, "Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial", Lancet, 359, pp.1734~1739 (2002)[DOI]
- Lo CM, "Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma", Hepatology, 35, pp.1164~1171 (2002)[DOI]
- Murata S, "Interventional treatment for unresectable hepatocellular carcinoma", World J Gastroenterol, 20, pp.13453~13465 (2014)[DOI]
- Shaaban S, "Chemotherapeutic agent for the treatment of hepatocellular carcinoma: efficacy and mode of action", Oncol Rev, 8, pp.25~35 (2014)
- Gupta SC, "Chemosensitization of tumors by resveratrol", Ann NY Acad Sci, 1215, pp.150~160 (2011)[DOI]
- Sale S, "Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4'-tetramethoxystilbene (DMU-212) on adenoma development in the Apc (Min+) mouse and cyclooxygenase-2 in human-derived colon cancer cells", Int J Cancer, 115, pp.194~201 (2005)[DOI]
- Newsholme E, "The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells", Biosci Rep, 5, pp.393~400 (1985)[DOI]
- Wellen KE, "The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism", Genes Dev, 24, pp.2784~2799 (2010)[DOI]
- Kueck A, "Resveratrol inhibits glucose metabolism in human ovarian cancer cells", Gynecol Oncol, 107, pp.450~457 (2007)[DOI]
- Park JB, "Inhibition of glucose and dehydroascorbic acid uptakes by resveratrol in human transformed myelocytic cells", J Nat Prod, 64, pp.381~384 (2001)[DOI]
- Hwang SO, "Nutrient deprivation induces autophagy as well as apoptosis in chinese hamster ovary cell culture", Biotechnol Bioeng, 99, pp.678~685 (2008)[DOI]
- Hassan M, "Apoptosis and molecular targeting therapy in cancer", Biomed Res Int, 2, pp.1~23 (2014)
- Chou TC, "Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors", Adv Enzyme Regul, 22, pp.27~55 (1984)[DOI]
- Bjorklund M, "Resveratrol induces SIRT1- and energy-stress-independent inhibition of tumor cell regrowth after low-dose platinum treatment", Cancer Chemother Pharmacol, 68, pp.1459~1467 (2011)[DOI]
- Desoize B, "Particular aspects of platinum compounds used at present in cancer treatment", Crit Rev Oncol Hematol, 42, pp.317~325 (2002)[DOI]
- Todd RC, "Inhibition of transcription by platinum antitumor compounds", Metallomics, 1, pp.280~291 (2009)[DOI]
- Wu YJ, "The chemoprotective agent N-acetylcysteine blocks cisplatininduced apoptosis through caspase signaling pathway", J Pharmacol Exp Ther, 312, pp.424~431 (2005)
- Ma L, "Resveratrol enhanced anticancer effects of cisplatin on non-small cell lung cancer cell lines by inducing mitochondrial dysfunction and cell apoptosis", Int J Oncol, 47, pp.1460~1468 (2015)[DOI]
- Wang J, "Resveratrol protects against cisplatin-induced cardiotoxicity by alleviating oxidative damage", Cancer Biother Radiopharm, 24, pp.675~680 (2009)[DOI]
- Simsek G, "Protective effects of resveratrol on cisplatin-dependent inner-ear damage in rats", Eur Arch Otorhinolaryngol, 270, pp.1789~1793 (2013)[DOI]
- Kim D, "SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53", Am J Physiol Renal Physiol, 301, pp.F427~F435 (2011)[DOI]
- De Oliveira MR, "Resveratrol and the mitochondria: from triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view", Biochim Biophys Acta, 1860, pp.727~745 (2016)[DOI]
- Huang Y, "Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance", Cancer Res, 64, pp.4294~4301 (2004)[DOI]
- Wise DR, "Glutamine addiction: a new therapeutic target in cancer", Trends BiochemSci, 35, pp.427~433 (2010)[DOI]
- Bode BP, "Molecular and functional analysis of glutamine uptake in human hepatoma and liver-derived cells", Am J Physiol Gastrointest Liver Physiol, 283, pp.G1062~G1073 (2002)[DOI]
- Wang Q, "Targeting glutamine transport to suppress melanoma cell growth", Int J Cancer, 135, pp.1060~1071 (2014)[DOI]
- Willems L, "Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia", Blood, 122, pp.3521~3532 (2013)[DOI]
- Hassanein M, "SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival", Clin Cancer Res, 19, pp.560~570 (2013)[DOI]
- Ren P, "ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation", J Pathol, 235, pp.90~100 (2015)[DOI]
- Kaira K, "Clinicopathological significance of ASC-amino acid transporter 2 (ASCT2) expression in pancreatic ductal carcinoma", Histopathology, 66, pp.234~243 (2015)[DOI]
- Brozovic A, "Activation of mitogenactivated protein kinases by cisplatin and their role in cisplatin-resistance", Cancer Lett, 251, pp.1~16 (2007)[DOI]
- Efeyan A, "p53: guardian of the genome and policeman of the oncogenes", Cell Cycle, 6, pp.1006~1010 (2007)[DOI]
- De Laurenzi V, "Evolution of functions within the p53", p63, Ann NY Acad Sci, pp.2000, 926[DOI]
- Kutuk O, "Cisplatin overcomes Bcl-2-mediated resistance to apoptosis via preferential engagement of Bak: critical role of Noxa-mediated lipid peroxidation", Carcinogenesis, 30, pp.1517~1527 (2009)[DOI]
- Santandreu FM, "Resveratrol potentiates the cytotoxic oxidative stress induced by chemotherapy in human colon cancer cells", Cell Physiol Biochem, 28, pp.219~228 (2011)[DOI]