Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells
Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells
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Hsp90 抑制剂 17-AAG 通过抑制肝细胞癌细胞中 ERK 介导的保护性自噬和 Mcl-1 积累来增敏 Bcl-2 抑制剂 (-)-棉酚
DOI：
10.1016/j.yexcr.2014.08.039
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发表时间：
2014-11-01
影响因子：
3.7
通讯作者：
He, Fengtian
中科院分区：
文献类型：
--
作者：
Wang, Bin;Chen, Linfeng;He, Fengtian
天然BH_3-memitic（-）-gossypol对多种肿瘤具有良好的抗肿瘤作用。然而，我们以前的研究表明，保护性自噬降低了肝细胞癌（HCC）细胞中Bcl-2抑制剂的药物敏感性。在本研究中，我们首次报道了Hsp 90抑制剂17-AAG通过抑制（-）-棉酚引发的保护性自噬和Mcl-1积累来增强（-）-棉酚诱导的细胞凋亡。17-AAG对自噬的抑制作用是通过抑制ERK介导的Bcl-2磷酸化而介导的，而与Beclin 1或LC 3蛋白的不稳定性无关。同时，17-AAG通过抑制Mcl-1（Thr 163）磷酸化和促进蛋白降解来下调（-）-棉酚触发的Mcl-1积累。总之，我们的研究表明，Hsp 90在肿瘤维持中起着重要作用，抑制Hsp 90可能成为HCC细胞中Bcl-2靶向化疗增敏的新策略。(C)2014爱思唯尔公司All rights reserved.
Natural BH3-memitic (-)-gossypol shows promising antitumor efficacy in several kinds of cancer. However, our previous studies have demonstrated that protective autophagy decreases the drug sensitivities of Bcl-2 inhibitors in hepatocellular carcinoma (HCC) cells. In the present study, we are the first to report that Hsp90 inhibitor 17-AAG enhanced (-)-gossypol-induced apoptosis via suppressing (-)-gossypol-triggered protective autophagy and Mcl-1 accumulation. The suppression effect of 17-AAG on autophagy was mediated by inhibiting ERK-mediated Bcl-2 phosphorylation while was not related to Beclin1 or LC3 protein instability. Meanwhile, 17-AAG downregulated (-)-gossypol-triggered Mcl-1 accumulation by suppressing Mcl-1(Thr163) phosphorylation and promoting protein degradation. Collectively, our study indicates that Hsp90 plays an important role in tumor maintenance and inhibition of Hsp90 may become a new strategy for sensitizing Bcl-2-targeted chemotherapies in HCC cells. (C) 2014 Elsevier Inc. All rights reserved.