01Two paths to cell death
Apoptosis is tidy, programmed cell death: the cell shrinks, DNA fragments, and neighbors engulf the remains without inflammation. The intrinsic (mitochondrial) pathway responds to internal stress like DNA damage. The extrinsic pathway starts when death ligands (FasL, TRAIL) bind death receptors on the surface.
Both converge on caspases — proteases that dismantle the cell. Initiators (caspase-8 extrinsic, caspase-9 intrinsic) activate executioners (caspase-3, -7).
02The BCL-2 family decides
In the intrinsic pathway, BAX and BAK punch holes in the mitochondrial outer membrane, releasing cytochrome c. Cytochrome c joins APAF-1 to form the apoptosome, activating caspase-9. Anti-apoptotic proteins BCL-2, BCL-XL and MCL-1 block BAX/BAK; 'BH3-only' sensors (BIM, PUMA, NOXA) tip the balance toward death.
BCL-2 was discovered at the t(14;18) translocation in follicular lymphoma — the first oncogene shown to work by preventing death rather than increasing division.
03Fighting back
Venetoclax is a BH3-mimetic that blocks BCL-2, unleashing apoptosis in chronic lymphocytic leukemia and AML. Cancer cells also evade death by losing p53, overexpressing IAPs (inhibitors of apoptosis) or downregulating death receptors.