Bim and VDAC1 are hierarchically essential for mitochondrial ATF2 mediated cell death

Cancer Cell International

Chunbao Guo¹  Qianfu Luo²  Zhaoyun Liu² 

[1] Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P. R. China;Laboratory of Surgery, Children’s Hospital of Chongqing Medical University, 136 Zhongshan 2nd Rd, Chongqing 400014, P. R. China

关键词: Apoptosis;    VDAC1;    Bim;    ATF2;    Mitochondria;   

Others  :  1171059
DOI  :  10.1186/s12935-015-0188-y

 received in 2015-01-18, accepted in 2015-03-20,  发布年份 2015

【 摘 要 】

Background

ATF2 mediated cytochrome c release is the formation of a channel with some unknown factors larger than that of the individual proteins. BHS-only proteins (BH3s), such as Bim, could induce BAX and VDAC, forming a new channel. According to this facts, we can speculated that there is possible signal relationship with BH3s and ATF2, which is associated with mitochondrial-based death programs.

Methods

The growth inhibitory effects of mitochondrial ATF2 were tested in cancer cell lines B16F10, A549, EG7, and LL2. Apoptosis was measured by flow cytometry. The effects of ATF2 and levels of apoptosis regulatory proteins were measured by Western blotting. The interaction of proteins were evaluated by immunoprecipitation analysis. The in vivo antitumor activity of mitochondrial ATF2 were tested in xenograft B16F10 models.

Results

Genotoxic stress enabled mitochondrial ATF2 accumulation, perturbing the HK1-VDAC1 complex, increasing mitochondrial permeability, and promoting apoptosis. ATF2 inhibition strongly reduced the conformational activation of Bim, suggesting that Bim acts downstream of ATF2. Although Bim downregulation had no effect on ATF2 activation, Bim knockdown abolished VDAC1 activation; the failure of VDAC1 activation in Bim-depleted cells could be reversed by the BH3-only protein mimic ABT-737. We also demonstrate that silencing of ATF2 in B16F10 cells increases both the incidence and prevalence of tumor xenografts in vivo, whereas stably mitochondrial ATF2 transfection inhibited B16F10 tumor xenografts growth.

Conclusions

Altogether, these results show that ATF2 is a component of the apoptosis machinery that involves a hierarchical contribution of ATF2, Bim, and VDAC1. Our data offer new insight into the mechanism of mitochondrial ATF2 in mitochondrial apoptosis.

【 授权许可】

   
2015 Liu et al.; licensee BioMed Central.

【 图 表 】

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