Fan Guang-Hua, Wang Zhong-Ming, Yang Xi, Xu Li-Ping, Qin Qin, Zhang Chi, Ma Jian-Xin, Cheng Hong-Yan, Sun Xin-Chen
Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China E-mail :
Asian Pac J Cancer Prev. 2014;15(2):677-82. doi: 10.7314/apjcp.2014.15.2.677.
Resveratrol has been examined in several model systems for potential effects against cancer. Adenosine monophosphate-activated protein kinase (AMPK) is reported to suppress proliferation in most eukaryocyte cells. Whether resveratrol via AMPK inhibits proliferation of oesophageal adenocarcinoma cells (OAC) is unknown. The aim of this study was to determine the roles of AMPK in the protective effects of resveratrol in OAC proliferation and to elucidate the underlying mechanisms. Treatment of cultured OAC derived from human subjects or cell lines with resveratrol resulted in decreased cell proliferation. Further, inhibition of AMPK by pharmacological reagent or genetical approach abolished resveratrol-suppressed OAC proliferation, reduced the level of p27Kip1, a cyclin-dependent kinase inhibitor, and increased the levels of S-phase kinase-associated protein 2 (Skp2) of p27Kip1-E3 ubiquitin ligase and 26S proteasome activity reduced by resveratrol. Furthermore, gene silencing of p27Kip1 reversed resveratrol-suppressed OAC proliferation. In conclusion, these findings indicate that resveratrol inhibits Skp2-mediated ubiquitylation and 26S proteasome-dependent degradation of p27Kip1 via AMPK activation to suppress OAC proliferation.
白藜芦醇已在多个模型系统中进行了研究，以探讨其对癌症的潜在作用。据报道，单磷酸腺苷激活的蛋白激酶（AMPK）可抑制大多数真核细胞的增殖。白藜芦醇是否通过AMPK抑制食管腺癌细胞（OAC）的增殖尚不清楚。本研究的目的是确定AMPK在白藜芦醇对OAC增殖的保护作用中的作用，并阐明其潜在机制。用白藜芦醇处理源自人类受试者或细胞系的培养OAC会导致细胞增殖减少。此外，通过药理学试剂或基因方法抑制AMPK可消除白藜芦醇抑制的OAC增殖，降低细胞周期蛋白依赖性激酶抑制剂p27Kip1的水平，并增加白藜芦醇降低的p27Kip1-E3泛素连接酶的S期激酶相关蛋白2（Skp2）水平和26S蛋白酶体活性。此外，p27Kip1基因沉默可逆转白藜芦醇抑制的OAC增殖。总之，这些发现表明白藜芦醇通过激活AMPK抑制Skp2介导的p27Kip1泛素化和26S蛋白酶体依赖性降解，从而抑制OAC增殖。
