Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells
Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells
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AMP 激活蛋白激酶 (AMPK) 的激活介导白花丹素诱导的人结肠癌细胞凋亡和生长抑制
DOI：
10.1016/j.cellsig.2013.05.026
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发表时间：
2013-10-01
影响因子：
4.8
通讯作者：
Lu, Pei-Hua
中科院分区：
文献类型：
--
作者：
Chen, Min-Bin;Zhang, Yan;Lu, Pei-Hua
在这里，我们报告的AMP激活蛋白激酶（AMPK）的激活介导的白花丹素诱导的细胞凋亡和生长抑制在原代培养的人结肠癌细胞和细胞系。通过靶shRNA敲低AMPK α显著抑制了培养的结肠癌细胞中白花丹素诱导的细胞毒性，而通过引入组成型活性AMPK（CA-AMPK）或通过AMPK激活剂强制激活AMPK抑制HT-29结肠癌细胞生长。我们的Western印迹和免疫沉淀（IP）结果表明，白花丹素诱导AMPK/凋亡信号调节激酶1（ASK 1）/TNF受体相关因子2（TRAF 2）联合激活促凋亡c-Jun N末端激酶（JNK）-p53信号轴。此外，在白花丹素处理后，活化的AMPK直接磷酸化Raptor以抑制结肠癌细胞中的mTOR复合物1（mTORC 1）活化和Bcl-2表达。最后，我们发现外源性短链神经酰胺（C6）增强白花丹素诱导的AMPK激活，促进细胞凋亡和生长抑制。我们的研究结果表明，AMPK可能是白花丹素抗肿瘤活性的关键介质。(C)2013年由Elsevier Inc.出版
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.