Resveratrol inhibits proliferation of hepatoma cells <i>via</i> PI3K p85/Akt signaling axis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHOU Kejun ^1,2 ,  WANG Cheng ¹ , XIE Mengyi ² , HOU Yongchuan ³ , XIONG Yunlin ³ , LIU Yu ¹ , DENG Lin ¹

1. Department of Pediatric Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Hepatobiliary Research Institute of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
3. North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

WANG Cheng, Email: wangchengemail@126.com

Keywords：

resveratrol; HepG2 cell; phosphatidylinositol 3-kinase p85; protein kinase B; proliferation

DOI：

10.7507/1007-9424.201910006

Video：

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Objective This study aims to study the effects and mechanism of resveratrol on hepatocellular carcinoma (HCC) cells through phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis.Methods HepG2 cells at logarithmic growth stage were treated with different concentrations (0, 12.5, 25.0, and 50.0 μmol/L) of resveratrol, respectively. Then the proliferation of HepG2 cells was detected by the CCK8 method and real time cell anaIysis (RTCA) system, the expressions of signal molecules associated with PI3K/Akt axis was detected by the Western blot method, including PI3K p58, phosphorylation protein kinase B (p-Akt), total protein kinase B (t-Akt), and CyclinA2 protein.Results Resveratrol had a significant inhibitory effect on the growth of HepG2 cells in a time and dosage dependent manner. After 48 h treatment of resveratrol to HepG2 cells, 50.0 μmol/L resveratrol inhibited the growth of HepG2 cells most significantly. Further, the RTCA system studies also found that resveratrol had a time and concentration dependent effect on the reduction of normalized cell index (NCI) in HepG2 cells. Flow cytometry results showed that, apoptosis rates of 12.5, 25.0, and 50.0 μmol/L group were higher than that of 0 μmol/L group. Compard with 0 μmol/L group, the expressions of PI3K p85, p-Akt, and CyclinA2 protein in HepG2 cells of 12.5, 25.0, and 50.0 μmol/L resveratrol group was significantly higher (P<0.05), although there was no significant effect of resveratrol on the expression of t-Akt in HepG2 cells (P>0.05).Conclusions Resveratrol might have anti-proliferation effects on HepG2 cells through PI3K p85/Akt signaling axis. This study could provide a novel idea for the treatment to HCC.

Citation： ZHOU Kejun, WANG Cheng, XIE Mengyi, HOU Yongchuan, XIONG Yunlin, LIU Yu, DENG Lin. Resveratrol inhibits proliferation of hepatoma cells via PI3K p85/Akt signaling axis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(7): 808-813. doi: 10.7507/1007-9424.201910006 Copy

1.	Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
2.	Vagianos C, Karavias D, Dragotis C, et al. Obstructive jaundice due to intracholedochal blood clot: an unusual early presentation of primary hepatic carcinoma. Br J Clin Pract, 1993, 47(4): 222-223.
3.	Wu L, Wu J, Zhang H. Hypoglycemia-induced convulsive status epilepticus as the initial presentation of primary hepatic carcinoma. Neurol Sci, 2012, 33(6): 1469-1471.
4.	中华人民共和国卫生和计划生育委员会医政医管局. 原发性肝癌诊疗规范 (2017 年版). 中华肝脏病杂志, 2017, 25(12): 886-895.
5.	Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
6.	梁睿, 翟溯澜, 王柳燕, 等. 白藜芦醇调控 miR-519c 逆转乳腺癌多柔比星耐药作用机制研究. 中华肿瘤防治杂志, 2019, 26(15): 1066-1071.
7.	苗向霞, 郭蕊, 张璎, 等. 白藜芦醇对肝癌 HepG2 细胞中脂肪合成的抑制作用及其机制. 吉林大学学报: 医学版, 2019, 45(1): 69-72.
8.	赵宇, 祝瑜, 吴浪, 等. 白藜芦醇对人肝癌 HepG2 细胞增殖及自噬作用的影响. 中国生物制品学杂志, 2018, 31(6): 607-612.
9.	Rauf A, Imran M, Suleria HAR, et al. A comprehensive review of the health perspectives of resveratrol. Food Funct, 2017, 8(12): 4284-4305.
10.	Kovacic P, Somanathan R. Multifaceted approach to resveratrol bioactivity: focus on antioxidant action, cell signaling and safety. Oxid Med Cell Longev, 2010, 3(2): 86-100.
11.	Venturini CD, Merlo S, Souto AA, et al. Resveratrol and red wine function as antioxidants in the nervous system without cellular proliferative effects during experimental diabetes. Oxid Med Cell Longev, 2010, 3(6): 434-441.
12.	Kundu JK, Surh YJ. Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett, 2008, 269(2): 243-261.
13.	林春蕾, 何磊, 王凡, 等. 白藜芦醇的肝脏药理作用. 现代生物医学进展, 2013, 13(26): 5162-5164.
14.	胜利, 安利峰, 李覃, 等. 白藜芦醇抗肿瘤作用的研究进展. 医学综述, 2005, 11(7): 605-606.
15.	张兰胜, 刘光明. 白藜芦醇的研究概述. 大理学院学报, 2007, 6(4): 72-74, 80.
16.	闫静, 王振月, 刘丹宁, 等. 白藜芦醇及其甙的生物活性研究进展. 中医药学报, 2000, (2): 39-41.
17.	付招娣, 曹玉, 王凯风, 等. 白藜芦醇对癌的化学预防作用. 癌症, 2004, 23(8): 869-873.
18.	Delmas D, Rébé C, Lacour S, et al. Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J Biol Chem, 2003, 278(42): 41482-41490.
19.	Bishayee A, Barnes KF, Bhatia D, et al. Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis. Cancer Prev Res (Phila), 2010, 3(6): 753-763.
20.	朱青, 张王刚, 王立锋, 等. 白藜芦醇诱导肿瘤细胞凋亡和细胞周期阻滞的作用及机制. 医学争鸣, 2005, 26(21): 1935-1937.
21.	Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene, 2008, 27(41): 5497-5510.
22.	王晓辉, 李非, 郑亚民, 等. caveolin-1 通过阻断 PI3K/Akt 信号的激活抑制胰腺癌细胞增殖. 中国普外基础与临床杂志, 2011, 18(10): 1054-1059.
23.	Alkhalaf M. Resveratrol-induced apoptosis is associated with activation of p53 and inhibition of protein translation in T47D human breast cancer cells. Pharmacology, 2007, 80(2-3): 134-143.
24.	Zhang Y, Chen ML, Zhou Y, et al. Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res, 2015, 59(8): 1443-1457.
25.	Pozo-Guisado E, Lorenzo-Benayas MJ, Fernández-Salguero PM. Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation. Int J Cancer, 2004, 109(2): 167-173.
26.	孙中杰, 余海波, 张煜, 等. 白藜芦醇对裸鼠移植性肝癌的抑制作用. 陕西医学杂志, 2010, 39(3): 279-281.

1. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132.
2. Vagianos C, Karavias D, Dragotis C, et al. Obstructive jaundice due to intracholedochal blood clot: an unusual early presentation of primary hepatic carcinoma. Br J Clin Pract, 1993, 47(4): 222-223.
3. Wu L, Wu J, Zhang H. Hypoglycemia-induced convulsive status epilepticus as the initial presentation of primary hepatic carcinoma. Neurol Sci, 2012, 33(6): 1469-1471.
4. 中华人民共和国卫生和计划生育委员会医政医管局. 原发性肝癌诊疗规范 (2017 年版). 中华肝脏病杂志, 2017, 25(12): 886-895.
5. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015, 65(2): 87-108.
6. 梁睿, 翟溯澜, 王柳燕, 等. 白藜芦醇调控 miR-519c 逆转乳腺癌多柔比星耐药作用机制研究. 中华肿瘤防治杂志, 2019, 26(15): 1066-1071.
7. 苗向霞, 郭蕊, 张璎, 等. 白藜芦醇对肝癌 HepG2 细胞中脂肪合成的抑制作用及其机制. 吉林大学学报: 医学版, 2019, 45(1): 69-72.
8. 赵宇, 祝瑜, 吴浪, 等. 白藜芦醇对人肝癌 HepG2 细胞增殖及自噬作用的影响. 中国生物制品学杂志, 2018, 31(6): 607-612.
9. Rauf A, Imran M, Suleria HAR, et al. A comprehensive review of the health perspectives of resveratrol. Food Funct, 2017, 8(12): 4284-4305.
10. Kovacic P, Somanathan R. Multifaceted approach to resveratrol bioactivity: focus on antioxidant action, cell signaling and safety. Oxid Med Cell Longev, 2010, 3(2): 86-100.
11. Venturini CD, Merlo S, Souto AA, et al. Resveratrol and red wine function as antioxidants in the nervous system without cellular proliferative effects during experimental diabetes. Oxid Med Cell Longev, 2010, 3(6): 434-441.
12. Kundu JK, Surh YJ. Cancer chemopreventive and therapeutic potential of resveratrol: mechanistic perspectives. Cancer Lett, 2008, 269(2): 243-261.
13. 林春蕾, 何磊, 王凡, 等. 白藜芦醇的肝脏药理作用. 现代生物医学进展, 2013, 13(26): 5162-5164.
14. 胜利, 安利峰, 李覃, 等. 白藜芦醇抗肿瘤作用的研究进展. 医学综述, 2005, 11(7): 605-606.
15. 张兰胜, 刘光明. 白藜芦醇的研究概述. 大理学院学报, 2007, 6(4): 72-74, 80.
16. 闫静, 王振月, 刘丹宁, 等. 白藜芦醇及其甙的生物活性研究进展. 中医药学报, 2000, (2): 39-41.
17. 付招娣, 曹玉, 王凯风, 等. 白藜芦醇对癌的化学预防作用. 癌症, 2004, 23(8): 869-873.
18. Delmas D, Rébé C, Lacour S, et al. Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J Biol Chem, 2003, 278(42): 41482-41490.
19. Bishayee A, Barnes KF, Bhatia D, et al. Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis. Cancer Prev Res (Phila), 2010, 3(6): 753-763.
20. 朱青, 张王刚, 王立锋, 等. 白藜芦醇诱导肿瘤细胞凋亡和细胞周期阻滞的作用及机制. 医学争鸣, 2005, 26(21): 1935-1937.
21. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene, 2008, 27(41): 5497-5510.
22. 王晓辉, 李非, 郑亚民, 等. caveolin-1 通过阻断 PI3K/Akt 信号的激活抑制胰腺癌细胞增殖. 中国普外基础与临床杂志, 2011, 18(10): 1054-1059.
23. Alkhalaf M. Resveratrol-induced apoptosis is associated with activation of p53 and inhibition of protein translation in T47D human breast cancer cells. Pharmacology, 2007, 80(2-3): 134-143.
24. Zhang Y, Chen ML, Zhou Y, et al. Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway. Mol Nutr Food Res, 2015, 59(8): 1443-1457.
25. Pozo-Guisado E, Lorenzo-Benayas MJ, Fernández-Salguero PM. Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation. Int J Cancer, 2004, 109(2): 167-173.
26. 孙中杰, 余海波, 张煜, 等. 白藜芦醇对裸鼠移植性肝癌的抑制作用. 陕西医学杂志, 2010, 39(3): 279-281.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Resveratrol inhibits proliferation of hepatoma cells via PI3K p85/Akt signaling axis

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