Fig. 6
BCL-2 family members differ in their dependence on pro-apoptotic BH3-only members to exert their anti-apoptotic functions. In HCT116 cells, multiple BH3-only proteins, such as BIM, BID, BAD and PUMA are sequestered by BCL-XL, whereas NOXA is the only BH3-only protein bound to MCL-1. While the displacement of BH3-only proteins from BCL-XL following A-1331852 is sufficient to induce apoptosis in these cells, displacement of NOXA from MCL-1 following S63845 failed to induce apoptosis. However, the combination of A-1331852 and S63845 released all the BH3-only proteins from the anti-apoptotic counterparts and resulted in pronounced apoptosis (bold arrow). In the absence of all eight BH3-only proteins, neither A-1331852 nor S63845 alone resulted in apoptosis. However, a combination of A-1331852 and S63845 still resulted in pronounced apoptosis, even in the absence of all BH3-only proteins. This could be due to the release of another pro-apoptotic BH3 domain-containing ‘protein x’ from MCL-1 and/or BCL-XL, which in turn could activate BAX in the 8KO cells. Alternatively, BH3 mimetics could indirectly result in the accumulation of BAX (either by inhibition of retrotranslocation or by passive diffusion, following the neutralization of the anti-apoptotic members) in the outer mitochondrial membrane, which in turn could result in BAX activation and apoptosis in the 8KO cells
