Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells |
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Authors: | Min-Bin Chen Yan Zhang Mu-Xin Wei Wei Shen Xiao-Yang Wu Chen Yao Pei-Hua Lu |
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Institution: | 1. Department of Medical Oncology, Kunshan First People''s Hospital Affiliated to Jiangsu University, 91 Qianjin Road, Kunshan 215300, Jiangsu Province, China;2. Department of Traditional Chinese Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China;3. Department of General Surgery, Affiliated Wuxi People''s Hospital Affiliated to Nanjing Medical University, No. 299, Qingyang Road, Wuxi, 214023, Jiangsu, China;4. Department of General Surgery, Kunshan First People''s Hospital Affiliated to Jiangsu University, No. 91, Qianjin Road, Kunshan 215300, Jiangsu Province, China;5. Department of Orthopedics, BenQ Medical Center, Nanjing Medical University, 210019, Nanjing, Jiangsu, China |
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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. |
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