Anti-Tumorigenic Effect of Resveratrol in HepG2 cells Controlled with Cytochrome-c Dependent Cell Death Resveratrol and Cytochrome-c Dependent Cell Death in HepG2 cells
Main Article Content
Keywords
resveratrol, cancer, apoptosis, EMT
Abstract
Resveratrol is a phytochemical that regarded as potential anticancer agent in liver cancer prevention. It had also been shown that resveratrol has role in preventive of cancer and anti-cancer properties. In this study, we aimed to investigate the effects of resveratrol on cell viability, apoptosis, cellular proliferation, JAK/STAT pathway and epithelial-mesenchymal transition (EMT) in human hepatocellular carcinoma cell (HepG2) line. Cell growth and cytotoxicity were evaluated with MTT assay with different concentration (5, 10, 25, 50, 100 μM) of resveratrol in HepG2 cells. The distribution of FasL, cyt-c, caspase-3, Ki-67, ACTA2, CD133, JAK2, N-cadherin, vimentin and STAT3 in HepG2 cells were analyzed using indirect immunoperoxidase technique. The effective dose and incubation time for inhibition of cell growth in HepG2 cells was determined as 100 μM for 48 hours. Decreased Ki-67 immunureactivity following resveratrol application was significant in HepG2 cells. Increased cytc-c, STAT3, vimentin, N-cadherin and CD133 immunoreactivities were significant between resveratrol applicated HepG2 cells and control group. According to our results, resveratrol induced mitochondria-dependent cell death and suppressed proliferation in HepG2 cells. On the other hand, our results showed that resveratrol stimulated cellular self-protection responses through activation of EMT and STAT3 protein expression in HepG2 cells.
References
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31. Ko JH, Sethi G, Um JY, Shanmugam MK, Arfuso F, Kumar AP, Bishayee A, Ahn KS. The role of resveratrol in cancer therapy. International journal of molecular sciences 2017; 18:2589.
32. De Oliveira MR, Nabavi SF, Manayi A, Daglia M, Hajheydari Z, Nabavi SM. Resveratrol and the mitochondria: From triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochimica et Biophysica Acta (BBA)-General Subjects 2016; 1860:727-745.
33. Ou X, Chen Y, Cheng X, Zhang X, He Q. Potentiation of resveratrol-induced apoptosis by matrine in human hepatoma HepG2 cells. Oncology reports 2014; 32:2803-2809.
34. Ma X, Tian X, Huang X, Yan F, Qiao D. Resveratrol-induced mitochondrial dysfunction and apoptosis are associated with Ca 2+ and mCICR-mediated MPT activation in HepG2 cells. Molecular and cellular biochemistry 2007; 302:99-109.
35. Tang JJ, Thng DK, Lim JJ, Toh TB. JAK/STAT signaling in hepatocellular carcinoma. Hepatic oncology 2020; 7.
36. Murray PJ. The JAK-STAT signaling pathway: input and output integration. The Journal of Immunology 2007; 178:2623-2629.
37. Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Tan BK, Sethi G, Bishayee A. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochimica et Biophysica Acta (BBA)-reviews on cancer 2014; 1845:136-154.
38. Li WC, Ye SL, Sun RX, Liu YK, Tang ZY, Kim Y, Karras JG, Zhang H. Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clinical Cancer Research 2006; 12:7140-7148.
39. Zhang CH, Guo FL, Xu GL, Jia WD, Ge YS. STAT3 activation mediates epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells. Hepato-gastroenterology 2014; 61:1082-1089.
40. Okusaka T, Ueno H, Ikeda M, Mitsunaga S, Ozaka M, Ishii H, Yokosuka O, Ooka Y, Yoshimoto R, Yanagihara Y, Okita K. Phase 1 and pharmacological trial of OPB‐31121, a signal transducer and activator of transcription‐3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatology Research 2015; 45:1283-1291.
41. Yoo C, Kang J, Lim HY, Kim JH, Lee MA, Lee KH, Kim TY, Ryoo BY. Phase I dose-finding study of OPB-111077, a novel STAT3 inhibitor, in patients with advanced hepatocellular carcinoma. Cancer research and treatment: official journal of Korean Cancer Association 2019; 51:510.
42. Li Y, Zhu W, Li J, Liu M, Wei M. Resveratrol suppresses the STAT3 signaling pathway and inhibits proliferation of high glucose-exposed HepG2 cells partly through SIRT1. Oncology reports 2013; 30:2820-2828.
43. Trung LQ, Espinoza JL, Takami A, Nakao S. Resveratrol induces cell cycle arrest and apoptosis in malignant NK cells via JAK2/STAT3 pathway inhibition. PloS one 2013; 8:e55183.
44. Tomaskovic-Crook E, Thompson EW, Thiery JP. Epithelial to mesenchymal transition and breast cancer. Breast Cancer Research 2009; 11:1-0.
45. Yang HL, Chen WQ, Cao X, Worschech A, Du LF, Fang WY, Xu YY, Stroncek DF, Li X, Wang E, Marincola FM. Caveolin-1 enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model. Journal of Translational Medicine 2009; 7:1-3.
46. Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. The international journal of biochemistry & cell biology 2012; 44:2144-2151.
47. Colin D, Lancon A, Delmas D, Lizard G, Abrossinow J, Kahn E, Jannin B, Latruffe N. Antiproliferative activities of resveratrol and related compounds in human hepatocyte derived HepG2 cells are associated with biochemical cell disturbance revealed by fluorescence analyses. Biochimie 2008; 90:1674-1684.
48. Li LT, Jiang G, Chen Q, Zheng JN. Ki67 is a promising molecular target in the diagnosis of cancer. Molecular medicine reports 2015; 11:1566-1572.
2. Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 2017; 152:745-61.
3. Alqahtani A, Khan Z, Alloghbi A, S Said Ahmed T, Ashraf M, M Hammouda D. Hepatocellular carcinoma: molecular mechanisms and targeted therapies. Medicina 2019; 55:526.
4. Cha C, DeMatteo RP. Molecular mechanisms in hepatocellular carcinoma development. Best practice & research Clinical gastroenterology 2005; 19:25-37.
5. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008; 134:1752-63.
6. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, De Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M. Sorafenib in advanced hepatocellular carcinoma. New England journal of medicine 2008; 359:378-90.
7. Ramos S. Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Molecular nutrition & food research 2008; 52:507-526.
8. Bishayee A, Politis T, Darvesh AS. Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma. Cancer treatment reviews 2010; 36:43-53.
9. Kocsis Z, Marcsek ZL, Jakab MG, Szende B, Tompa A. Chemopreventive properties of trans-resveratrol against the cytotoxicity of chloroacetanilide herbicides in vitro. International journal of hygiene and environmental health 2005; 208:211-218.
10. Stervbo U, Vang O, Bonnesen C. Time‐and concentration‐dependent effects of resveratrol in HL‐60 and HepG2 cells. Cell Proliferation 2006; 39:479-493.
11. Notas G, Nifli AP, Kampa M, Vercauteren J, Kouroumalis E, Castanas E. Resveratrol exerts its antiproliferative effect on HepG2 hepatocellular carcinoma cells, by inducing cell cycle arrest, and NOS activation. Biochimica et Biophysica Acta (BBA)-General Subjects 2006; 1760:1657-1666.
12. Yu H, Pan C, Zhao S, Wang Z, Zhang H, Wu W. Resveratrol inhibits tumor necrosis factor-α-mediated matrix metalloproteinase-9 expression and invasion of human hepatocellular carcinoma cells. Biomedicine & pharmacotherapy 2008; 62:366-372.
13. Sun ZJ, Pan CE, Liu HS, Wang GJ. Anti-hepatoma activity of resveratrol in vitro. World journal of gastroenterology 2002; 8:79.
14. Michels G, Wätjen W, Weber N, Niering P, Chovolou Y, Kampkötter A, Proksch P, Kahl R. Resveratrol induces apoptotic cell death in rat H4IIE hepatoma cells but necrosis in C6 glioma cells. Toxicology 2006; 225:173-82.
15. Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. Journal of hepatology 2016; 65:798-808.
16. Gurzu S, Kobori L, Fodor D, Jung I. Epithelial mesenchymal and endothelial mesenchymal transitions in hepatocellular carcinoma: a review. BioMed research international 2019.
17. Seo DD, Lee HC, Kim HJ, Min HJ, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ, Yu E, Chun SY. Neural cadherin overexpression is a predictive marker for early postoperative recurrence in hepatocellular carcinoma patients. Journal of gastroenterology and hepatology 2008; 23:1112-1118.
18. Yamanaka C, Wada H, Eguchi H, Hatano H, Gotoh K, Noda T, Yamada D, Asaoka T, Kawamoto K, Nagano H, Doki Y. Clinical significance of CD13 and epithelial mesenchymal transition (EMT) markers in hepatocellular carcinoma. Japanese journal of clinical oncology 2018; 48:52-60.
19. Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, Peng WL, Wu JC. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology 2009; 50:1464-1474.
20. Zhai X, Zhu H, Wang W, Zhang S, Zhang Y, Mao G. Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC. Medical oncology 2014; 31:1-9.
21. Kim J, Hong SJ, Park JY, Park JH, Yu YS, Park SY, Lim EK, Choi KY, Lee EK, Paik SS, Lee KG. Epithelial–mesenchymal transition gene signature to predict clinical outcome of hepatocellular carcinoma. Cancer science 2010; 101:1521-1528.
22. Mima K, Hayashi H, Kuroki H, Nakagawa S, Okabe H, Chikamoto A, Watanabe M, Beppu T, Baba H. Epithelial-mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: Clinical significance of transforming growth factor-β signaling. Oncology letters 2013; 5:149-154.
23. Li YM, Xu SC, Li J, Han KQ, Pi HF, Zheng L, Zuo GH, Huang XB, Li HY, Zhao HZ, Yu ZP. Epithelial–mesenchymal transition markers expressed in circulating tumor cells in hepatocellular carcinoma patients with different stages of disease. Cell death & disease 2013; 4:e831.
24. Huber MA, Beug H, Wirth T. Epithelial-mesenchymal transition: NF-κB takes center stage. Cell cycle 2004; 3:1477-1480.
25. Maier HJ, Schmidt-Straßburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-κB promotes epithelial–mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer letters 2010; 295:214-228.
26. Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, Jiang H, Ren J, Cai J, Li Q. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC cancer 2015; 15:1-2.
27. Wang H, Zhang H, Tang L, Chen H, Wu C, Zhao M, Yang Y, Chen X, Liu G. Resveratrol inhibits TGF-β1-induced epithelial-to-mesenchymal transition and suppresses lung cancer invasion and metastasis. Toxicology 2013; 303:139-146.
28. Hoca M, Becer E, Kabadayı H, Yücecan S, Vatansever HS. The effect of resveratrol and quercetin on epithelial-mesenchymal transition in pancreatic cancer stem cell. Nutrition and cancer 2020; 72:1231-1242.
29. Li W, Ma J, Ma Q, Li B, Han L, Liu J, Xu Q, Duan W, Yu S, Wang F, Wu E. Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway. Current medicinal chemistry 2013; 20:4185-4194.
30. Özsoy S, Becer E, Kabadayı H, Vatansever HS, Yücecan S. Quercetin-Mediated apoptosis and cellular senescence in human colon cancer. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 2020; 20:1387-1396.
31. Ko JH, Sethi G, Um JY, Shanmugam MK, Arfuso F, Kumar AP, Bishayee A, Ahn KS. The role of resveratrol in cancer therapy. International journal of molecular sciences 2017; 18:2589.
32. De Oliveira MR, Nabavi SF, Manayi A, Daglia M, Hajheydari Z, Nabavi SM. Resveratrol and the mitochondria: From triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochimica et Biophysica Acta (BBA)-General Subjects 2016; 1860:727-745.
33. Ou X, Chen Y, Cheng X, Zhang X, He Q. Potentiation of resveratrol-induced apoptosis by matrine in human hepatoma HepG2 cells. Oncology reports 2014; 32:2803-2809.
34. Ma X, Tian X, Huang X, Yan F, Qiao D. Resveratrol-induced mitochondrial dysfunction and apoptosis are associated with Ca 2+ and mCICR-mediated MPT activation in HepG2 cells. Molecular and cellular biochemistry 2007; 302:99-109.
35. Tang JJ, Thng DK, Lim JJ, Toh TB. JAK/STAT signaling in hepatocellular carcinoma. Hepatic oncology 2020; 7.
36. Murray PJ. The JAK-STAT signaling pathway: input and output integration. The Journal of Immunology 2007; 178:2623-2629.
37. Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Tan BK, Sethi G, Bishayee A. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochimica et Biophysica Acta (BBA)-reviews on cancer 2014; 1845:136-154.
38. Li WC, Ye SL, Sun RX, Liu YK, Tang ZY, Kim Y, Karras JG, Zhang H. Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clinical Cancer Research 2006; 12:7140-7148.
39. Zhang CH, Guo FL, Xu GL, Jia WD, Ge YS. STAT3 activation mediates epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells. Hepato-gastroenterology 2014; 61:1082-1089.
40. Okusaka T, Ueno H, Ikeda M, Mitsunaga S, Ozaka M, Ishii H, Yokosuka O, Ooka Y, Yoshimoto R, Yanagihara Y, Okita K. Phase 1 and pharmacological trial of OPB‐31121, a signal transducer and activator of transcription‐3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatology Research 2015; 45:1283-1291.
41. Yoo C, Kang J, Lim HY, Kim JH, Lee MA, Lee KH, Kim TY, Ryoo BY. Phase I dose-finding study of OPB-111077, a novel STAT3 inhibitor, in patients with advanced hepatocellular carcinoma. Cancer research and treatment: official journal of Korean Cancer Association 2019; 51:510.
42. Li Y, Zhu W, Li J, Liu M, Wei M. Resveratrol suppresses the STAT3 signaling pathway and inhibits proliferation of high glucose-exposed HepG2 cells partly through SIRT1. Oncology reports 2013; 30:2820-2828.
43. Trung LQ, Espinoza JL, Takami A, Nakao S. Resveratrol induces cell cycle arrest and apoptosis in malignant NK cells via JAK2/STAT3 pathway inhibition. PloS one 2013; 8:e55183.
44. Tomaskovic-Crook E, Thompson EW, Thiery JP. Epithelial to mesenchymal transition and breast cancer. Breast Cancer Research 2009; 11:1-0.
45. Yang HL, Chen WQ, Cao X, Worschech A, Du LF, Fang WY, Xu YY, Stroncek DF, Li X, Wang E, Marincola FM. Caveolin-1 enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model. Journal of Translational Medicine 2009; 7:1-3.
46. Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. The international journal of biochemistry & cell biology 2012; 44:2144-2151.
47. Colin D, Lancon A, Delmas D, Lizard G, Abrossinow J, Kahn E, Jannin B, Latruffe N. Antiproliferative activities of resveratrol and related compounds in human hepatocyte derived HepG2 cells are associated with biochemical cell disturbance revealed by fluorescence analyses. Biochimie 2008; 90:1674-1684.
48. Li LT, Jiang G, Chen Q, Zheng JN. Ki67 is a promising molecular target in the diagnosis of cancer. Molecular medicine reports 2015; 11:1566-1572.
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Becer E, Kıyak N, Vatansever HS, Kükner A. Anti-Tumorigenic Effect of Resveratrol in HepG2 cells Controlled with Cytochrome-c Dependent Cell Death : Resveratrol and Cytochrome-c Dependent Cell Death in HepG2 cells . Progr Nutr [Internet]. 2022 Mar. 28 [cited 2024 Jul. 18];24(1):e2022006. Available from: https://mattioli1885journals.com/index.php/progressinnutrition/article/view/11788
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How to Cite
1.
Becer E, Kıyak N, Vatansever HS, Kükner A. Anti-Tumorigenic Effect of Resveratrol in HepG2 cells Controlled with Cytochrome-c Dependent Cell Death : Resveratrol and Cytochrome-c Dependent Cell Death in HepG2 cells . Progr Nutr [Internet]. 2022 Mar. 28 [cited 2024 Jul. 18];24(1):e2022006. Available from: https://mattioli1885journals.com/index.php/progressinnutrition/article/view/11788
