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Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells

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Abstract

This report is designed to dissect the detail molecular mechanism by which dihydroartemisinin (DHA), a derivative of artemisinin, induces apoptosis in human hepatocellular carcinoma (HCC) cells. DHA induced a loss of the mitochondrial transmemberane potential (ΔΨm), release of cytochrome c, activation of caspases, and externalization of phosphatidylserine indicative of apoptosis induction. Compared with the modest inhibitory effects of silencing Bax, silencing Bak largely prevented DHA-induced ΔΨm collapse and apoptosis though DHA induced a commensurable activation of Bax and Bak, demonstrating a key role of the Bak-mediated intrinsic apoptosis pathway. DHA did not induce Bid cleavage and translocation from cytoplasm to mitochondria and had little effects on the expressions of Puma and Noxa, but did increase Bim and Bak expressions and decrease Mcl-1 expression. Furthermore, the cytotoxicity of DHA was remarkably reduced by silencing Bim, and modestly but significantly reduced by silencing Puma or Noxa. Silencing Bim or Noxa preferentially reduced DHA-induced Bak activation, while silencing Puma preferentially reduced DHA-induced Bax activation, demonstrating that Bim and to a lesser extent Noxa act as upstream mediators to trigger the Bak-mediated intrinsic apoptosis pathway. In addition, silencing Mcl-1 enhanced DHA-induced Bak activation and apoptosis. Taken together, our data demonstrate a crucial role of Bim in preferentially regulating the Bak/Mcl-1 rheostat to mediate DHA-induced apoptosis in HCC cells.

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Acknowledgments

The authors thank Dr. K. Taira for providing CFP-Bid plasmid and Dr. G. J. Gores for providing GFP Cyt.c plasmid. This work was supported by National Natural Science Foundation of China (Nos. 61178078, 81471699 and 61308111) and Guangzhou science and technology plan project (No. 2014J4100055).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China

    Guiqi Qin, ChuBiao Zhao, Lili Zhang, Hongyu Liu, Liuying Chai, Shengnan Wu & Tongsheng Chen

  2. Department of Pain Management, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, China

    Yingyao Quan & Xiaoping Wang

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  1. Guiqi Qin
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  2. ChuBiao Zhao
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Correspondence to Xiaoping Wang or Tongsheng Chen.

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Qin, G., Zhao, C., Zhang, L. et al. Dihydroartemisinin induces apoptosis preferentially via a Bim-mediated intrinsic pathway in hepatocarcinoma cells. Apoptosis 20, 1072–1086 (2015). https://doi.org/10.1007/s10495-015-1132-2

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