Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells.

Abstract

Here we report that activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in both primary cultured human colon cancer cells and cell lines. Knocking-down of AMPKα by the target shRNA significantly inhibits plumbagin-induced cytotoxicity in cultured colon cancer cells, while forced activation of AMPK by introducing a constitutively active AMPK (CA-AMPK), or by the AMPK activator, inhibits HT-29 colon cancer cell growth. Our Western-blots and immunoprecipitation (IP) results demonstrate that plumbagin induces AMPK/Apoptosis signal regulating kinase 1 (ASK1)/TNF receptor-associated factor 2 (TRAF2) association to activate pro-apoptotic c-Jun N-terminal kinases (JNK)-p53 signal axis. Further, after plumbagin treatment, activated AMPK directly phosphorylates Raptor to inhibit mTOR complex 1 (mTORC1) activation and Bcl-2 expression in colon cancer cells. Finally, we found that exogenously-added short-chain ceramide (C6) enhances plumbagin-induced AMPK activation and facilitates cell apoptosis and growth inhibition. Our results suggest that AMPK might be the key mediator of plumbagin's anti-tumor activity.

• Authors: Min-Bin Chen, Yan Zhang, Mu-Xin Wei, Wei Shen, Xiao-Yang Wu, Chen Yao, Pei-Hua Lu
• Journal: Cellular signalling (Cell Signal) Vol. 25 Issue 10 Pg. 1993-2002 (Oct 2013) ISSN: 1873-3913 [Electronic] England
• PMID: 23712032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• Naphthoquinones
• Reactive Oxygen Species
• AMP-Activated Protein Kinases
• plumbagin

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Antineoplastic Agents, Phytogenic
• Apoptosis (genetics)
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms (genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• HT29 Cells
• Humans
• Naphthoquinones (metabolism)
• Phosphorylation
• Primary Cell Culture
• Reactive Oxygen Species (metabolism)
• Signal Transduction (genetics)