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The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells
Cheng, P. Ni, Zhenhong Dai, Xufang Wang, Bin Ding, W. Smith, Amber Rae Xu, Liang Wu, D. He, Fengtian Lian, Jiqin
Cheng, P.
Ni, Zhenhong
Dai, Xufang
Wang, Bin
Ding, W.
Smith, Amber Rae
Xu, Liang
Wu, D.
He, Fengtian
Lian, Jiqin
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Abstract
Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces autophagy in several cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced autophagy through Beclin-1- and reactive oxygen species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced apoptosis and cell killing. Our results show that ApoG2 induced protective autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance cancer cell death through blocking ApoG2-stimulated autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted cancer therapy.
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Date
2013-02-07
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Nature Publishing Group
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Keywords
ApoG2, ROS, Autophagy, HCC
Citation
Cheng, P; Ni, Z; Dai, X; Wang, B; Ding, W; Smith, A Rae; Xu, L; Wu, D; He, F; & Lian, J; 2013 “The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells” Cell Death and Disease. 4, e489 http://dx.doi.org/10.1038/cddis.2013.17