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. 2022 Apr 20;8:215. doi: 10.1038/s41420-022-01009-1

Fig. 6. The proposed mechanism underlying synergistic cell death induction by ABT-199&PIs by transactivation of NOXA.

Fig. 6

Besides stabilization of TP53, proteasome inhibition by BTZ, CFZ, or IXZ prevents proteasomal degradation of the BH3-only protein NOXA. (I) The BH3-mimetic ABT-199 antagonizes the anti-apoptotic activity of BCL-2 thereby releaving BAX. (II) ABT-199 reduces activity of complexes I and II of the mitochondrial ETC mediating metabolic reprogramming that induces ISR manifesting in (P)-eIF2α and increased expression of ATF4 and ATF3. ATF3&ATF4 mediate transactivation of PMAIP1/NOXA that inhibits the anti-apoptotic activity of MCL-1. Thus, unrestrained effectors BAX and BAK are free to oligomerize and mediate mitochondrial outer membrane permeabilization (MOMP) that sets the intrinsic apoptosis machinery in motion.