期刊
CELLULAR SIGNALLING
卷 25, 期 10, 页码 1993-2002出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.05.026
关键词
AMP-activated protein kinase (AMPK); Plumbagin; Colon cancer
类别
资金
- National Natural Science Foundation [81101801, 81101676]
- Natural Science Foundation of Jiangsu Province [BK2010160, BK2011374]
- 9th Six Talents Peak Project of Jiangsu Province [WSN-012]
- Foundation of Wuxi Health Bureau [ZD1008]
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 AMPK alpha 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. (C) 2013 Published by Elsevier Inc.
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