S1, a Novel Pan-BH3 Mimetic, Induces Apoptosis in Mcl-1-Overexpressing Cells Through Bak

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  • Song Ting
    State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, People’s Republic of China State Key Laboratory of Natural and Biomimetic Drugs, Peking University, People’s Republic of China School of Life Science and Technology, Dalian University of Technology, People’s Republic of China
  • Chang Xilong
    School of Life Science and Technology, Dalian University of Technology, People’s Republic of China
  • Zhang Zhichao
    State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, People’s Republic of China
  • Liu Yubo
    School of Life Science and Technology, Dalian University of Technology, People’s Republic of China
  • Shen Xiaoyun
    School of Life Science and Technology, Dalian University of Technology, People’s Republic of China

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Abstract

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 S1 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 S1. 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.

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