Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville Melbourne, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville Melbourne, VIC, 3010, Australia.
Nat Commun. 2018 Nov 26;9(1):4976. doi: 10.1038/s41467-018-07309-4.
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.
内在凋亡对于防止肿瘤形成至关重要，许多抗癌药物通过这种方式来消除肿瘤细胞。BAX 和 BAK 是凋亡的两个必需介质，它们被认为通过相似的机制进行调节，并冗余地发挥作用以驱动细胞凋亡。通过无偏基因组范围的 CRISPR/Cas9 筛选，我们发现 VDAC2（电压依赖性阴离子通道 2）对于 BAX 的功能很重要，但对 BAK 没有影响。VDAC2 的基因缺失消除了 BAX 和 BAK 与含有 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。VDAC2 的缺失模拟了 BAX 的缺失，不仅损害了抗癌药物对肿瘤细胞的杀伤作用，还损害了抑制肿瘤形成的能力。总之，我们的研究表明，有效的 BAX 介导的凋亡依赖于 VDAC2，并揭示了 BAX 和 BAK 与其与 VDAC2 的相互作用在功能上受到影响的惊人差异。
