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.	中華人民共和國衛生和計劃生育委員會醫政醫管局. 原發性肝癌診療規范 (2017 年版). 中華肝臟病雜志, 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, 翟溯瀾, 王柳燕, 等. 白藜蘆醇調控 miR-519c 逆轉乳腺癌多柔比星耐藥作用機制研究. 中華腫瘤防治雜志, 2019, 26(15): 1066-1071.
7.	苗向霞, 郭蕊, 張瓔, 等. 白藜蘆醇對肝癌 HepG2 細胞中脂肪合成的抑制作用及其機制. 吉林大學學報: 醫學版, 2019, 45(1): 69-72.
8.	趙宇, 祝瑜, 吳浪, 等. 白藜蘆醇對人肝癌 HepG2 細胞增殖及自噬作用的影響. 中國生物制品學雜志, 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. 白藜蘆醇的肝臟藥理作用. 現代生物醫學進展, 2013, 13(26): 5162-5164.
14.	勝利, 安利峰, 李覃, 等. 白藜蘆醇抗腫瘤作用的研究進展. 醫學綜述, 2005, 11(7): 605-606.
15.	張蘭勝, 劉光明. 白藜蘆醇的研究概述. 大理學院學報, 2007, 6(4): 72-74, 80.
16.	閆靜, 王振月, 劉丹寧, 等. 白藜蘆醇及其甙的生物活性研究進展. 中醫藥學報, 2000, (2): 39-41.
17.	付招娣, 曹玉, 王凱風, 等. 白藜蘆醇對癌的化學預防作用. 癌癥, 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, 張王剛, 王立鋒, 等. 白藜蘆醇誘導腫瘤細胞凋亡和細胞周期阻滯的作用及機制. 醫學爭鳴, 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.	王曉輝, 李非, 鄭亞民, 等. caveolin-1 通過阻斷 PI3K/Akt 信號的激活抑制胰腺癌細胞增殖. 中國普外基礎與臨床雜志, 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.	孫中杰, 余海波, 張煜, 等. 白藜蘆醇對裸鼠移植性肝癌的抑制作用. 陜西醫學雜志, 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. 中華人民共和國衛生和計劃生育委員會醫政醫管局. 原發性肝癌診療規范 (2017 年版). 中華肝臟病雜志, 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, 翟溯瀾, 王柳燕, 等. 白藜蘆醇調控 miR-519c 逆轉乳腺癌多柔比星耐藥作用機制研究. 中華腫瘤防治雜志, 2019, 26(15): 1066-1071.
7. 苗向霞, 郭蕊, 張瓔, 等. 白藜蘆醇對肝癌 HepG2 細胞中脂肪合成的抑制作用及其機制. 吉林大學學報: 醫學版, 2019, 45(1): 69-72.
8. 趙宇, 祝瑜, 吳浪, 等. 白藜蘆醇對人肝癌 HepG2 細胞增殖及自噬作用的影響. 中國生物制品學雜志, 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. 白藜蘆醇的肝臟藥理作用. 現代生物醫學進展, 2013, 13(26): 5162-5164.
14. 勝利, 安利峰, 李覃, 等. 白藜蘆醇抗腫瘤作用的研究進展. 醫學綜述, 2005, 11(7): 605-606.
15. 張蘭勝, 劉光明. 白藜蘆醇的研究概述. 大理學院學報, 2007, 6(4): 72-74, 80.
16. 閆靜, 王振月, 劉丹寧, 等. 白藜蘆醇及其甙的生物活性研究進展. 中醫藥學報, 2000, (2): 39-41.
17. 付招娣, 曹玉, 王凱風, 等. 白藜蘆醇對癌的化學預防作用. 癌癥, 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, 張王剛, 王立鋒, 等. 白藜蘆醇誘導腫瘤細胞凋亡和細胞周期阻滯的作用及機制. 醫學爭鳴, 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. 王曉輝, 李非, 鄭亞民, 等. caveolin-1 通過阻斷 PI3K/Akt 信號的激活抑制胰腺癌細胞增殖. 中國普外基礎與臨床雜志, 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. 孫中杰, 余海波, 張煜, 等. 白藜蘆醇對裸鼠移植性肝癌的抑制作用. 陜西醫學雜志, 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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