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Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity.
Liu, Guijun; Shi, Aimin; Wang, Ningning; Li, Min; He, Xuxiao; Yin, Chunzhao; Tu, Qiaochu; Shen, Xia; Tao, Yongzhen; Wang, Qiang; Yin, Huiyong.
Affiliation
  • Liu G; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
  • Shi A; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China.
  • Wang N; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
  • Li M; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
  • He X; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China.
  • Yin C; University of the Chinese Academy of Sciences, CAS, Beijing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • Tu Q; University of the Chinese Academy of Sciences, CAS, Beijing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • Shen X; University of the Chinese Academy of Sciences, CAS, Beijing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • Tao Y; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, 200031, China. Electronic address: yztao01@sibs.ac.cn.
  • Wang Q; Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing, 100193, China. Electronic address: wangqiang06@caas.cn.
  • Yin H; CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, 200031, China; University of the Chinese Academy of Sciences, CAS, Beijing, China; Key Laboratory of Food Safety Risk Assessment, Ministry of H
Redox Biol ; 37: 101701, 2020 10.
Article in En | MEDLINE | ID: mdl-32863234
ABSTRACT
The well-documented anticarcinogenic properties of natural polyphenolic proanthocyanidins (OPC) have been primarily attributed to their antioxidant and anti-inflammatory potency. Emerging evidence suggests that OPC may target canonical oncogenic pathways, including PI3K/AKT; however, the underlying mechanism and therapeutic potential remain elusive. Here we identify that proanthocyanidin B2 (OPC-B2) directly binds and inhibits AKT activity and downstream signalling, thereby suppressing tumour cell proliferation and metabolism in vitro and in a xenograft and diethyl-nitrosamine (DEN)-induced hepatocellular carcinoma (HCC) mouse models. We further find that OPC-B2 binds to the catalytic and regulatory PH domains to lock the protein in a closed conformation, similar to the well-studied AKT allosteric inhibitor MK-2206. Molecular docking and dynamic simulation suggest that Lys297 and Arg86 are critical sites of OPC-B2 binding; mutation of Lys297 or Arg86 to alanine completely abolishes the antitumor effects of OPC-B2 but not MK-2206. Together, our study reveals that OPC-B2 is a novel allosteric AKT inhibitor with potent anti-tumour efficacy beyond its antioxidant and anti-inflammatory properties.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Proanthocyanidins / Liver Neoplasms Limits: Animals Language: En Journal: Redox Biol Year: 2020 Type: Article Affiliation country: China

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Proanthocyanidins / Liver Neoplasms Limits: Animals Language: En Journal: Redox Biol Year: 2020 Type: Article Affiliation country: China