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论文类型：期刊论文

发表时间：2012-08-01

发表刊物：JOURNAL OF PHARMACOLOGICAL SCIENCES

收录刊物：SCIE、PubMed、Scopus

卷号：119

期号：4

页面范围：330-340

ISSN号：1347-8613

关键字：BH3 mimetic; Bcl-2/Mcl-1 dual inhibitor; Mcl-1 dynamics; Bax; Bak

摘要：Mcl-1, an anti-apoptotic Bcl-2 homolog that has a structurally divergent BH3-binding pocket, non-redundant action model, and unique characteristic of short life confers complete resistance to the BH3 mimetic ABT-737. Herein, we used S1, previously identified as a Mcl-1/Bcl-2 dual inhibitor and a pure BH3 mimetic, to explore the mechanism of Mcl-1's action and supply a strategy to challenge Mcl-1's protection. Apoptosis assay in SMMC-7721, HCT116, and K562 cells demonstrated that SI can effectively challenge Mcl-1's anti-apoptotic effect. Notably, we discovered an unexpected dynamic change of Mcl-1 that directly correlates with resistance or commitment to apoptosis induced by both ABT-737 and Si. Co-immunoprecipitation assays demonstrated that Mcl-1 increase results from Bim trafficking from Bcl-2 to Mcl-1, while subsequent Bak released by S1 determines Mcl-1 decrease and full-blown apoptosis. Further experiments using Bak shRNA testified that Bak accounts for S1-induced apoptosis and Mcl-1 decrease. Consistently, Bax-deficient DU145 cells are sensitive to S1, whereas Bak-mutant MKN-28 cells are significantly more resistant. The in vitro model could be extended to an in vivo mouse xenograft model in which Mcl-1 confers resistance by increased protein level, and the release of Bak could serve as a biomarker of apoptosis. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.12103FP]