Proper execution of cell death ensures normal biological processes, and its deregulation causes human illness, ranging from cancer to neurodegenerative disorders. Three forms of cell death have been recognized based on morphological features: apoptosis, autophagic cell death, and necrosis. Among the three distinct forms of cell death, apoptosis is best studied. The BCL-2 family proteins are central regulators of apoptosis. Genetic loss-of-function studies reveal an essential axis of upstream “activator” BH3-only molecules and downstream BAX and BAK in activating mitochondrion-dependent apoptosis. In response to apoptotic signals, the “activator” BH3-only molecules, including BID, BIM, and PUMA, trigger the homo-oligomerization of multidomain proapoptotic BAX and BAK to permeabilize mitochondria, leading to the efflux of cytochrome c which in turn initiates the assembly of apoptosome complex for caspase activation.
We have recently explored the role of proapoptotic BCL-2 signaling cascades in oncogene inactivation-induced apoptosis and demonstrated that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in both HER2 amplified breast and EGFR mutant lung cancers. Mechanistically, we have delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of MEK-ERK leads to BIM induction, whereas antagonizing PI3K-AKT triggers nuclear translocation of FOXOs that directly activate the PUMA promoter. Induction of PUMA and BIM was further demonstrated in a doxycycline-inducible HER2 mouse breast tumor model following withdrawal of doxycycline to turn off the expression of HER2. More importantly, deficiency of Bim or Puma impaired caspase activation and thereby reduced tumor regression caused by inactivation of HER2. Along the same line, deficiency of Puma impeded the regression of EGFRL858R-driven mouse lung tumors upon inactivation of the EGFR mutant. Overall, our study identifies PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism-based anti-cancer strategies.