title: Resveratrol inhibits oesophageal adenocarcinoma cell proliferation via AMP-activated protein kinase signaling.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China E-mail : sunxinchen2012@163.com.
authors.forename: Guang-Hua
authors.initials: GH
authors.lastname: Fan
authors.forename: Zhong-Ming
authors.initials: ZM
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Xu
authors.forename: Qin
authors.initials: Q
authors.lastname: Qin
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Ma
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Cheng
authors.forename: Xin-Chen
authors.initials: XC
authors.lastname: Sun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D054875:Ubiquitination
chemical_list: D016588:Anticarcinogenic Agents; C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D013267:Stilbenes; D055372:AMP-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000077185:Resveratrol