Intrinsic apoptosis is critical to prevent tumor formation and is engaged by many anti-cancer agents to eliminate tumor cells. BAX and BAK, the two essential mediators of apoptosis, are thought to be regulated through similar mechanisms and act redundantly to drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not BAK, to function. Genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes containing VDAC1, VDAC2, and VDAC3, but only inhibited BAX apoptotic function. Deleting VDAC2 phenocopied the loss of BAX in impairing both the killing of tumor cells by anti-cancer agents and the ability to suppress tumor formation. Together, our studies show that efficient BAX-mediated apoptosis depends on VDAC2, and reveal a striking difference in how BAX and BAK are functionally impacted by their interactions with VDAC2.

中文翻译：

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VDAC2使BAX能够介导凋亡并限制肿瘤的发展。

内在凋亡对防止肿瘤形成至关重要，并与许多抗癌药物共同消除肿瘤细胞。BAX和BAK是细胞凋亡的两个重要介体，被认为可以通过相似的机制进行调节，并多余地发挥作用，从而导致凋亡性细胞死亡。从无偏见的全基因组CRISPR / Cas9筛选中，我们确定了VDAC2（电压依赖性阴离子通道2）对BAX起作用但对BAK起作用不重要。VDAC2的遗传删除取消了BAX和BAK与包含VDAC1，VDAC2和VDAC3的线粒体复合物的关联，但仅抑制了BAX的凋亡功能。删除VDAC2表型复制了BAX的丧失，从而损害了抗癌药杀死肿瘤细胞和抑制肿瘤形成的能力。总之，我们的研究表明，有效的BAX介导的细胞凋亡取决于VDAC2，