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Global cleavage of cellular proteins by activated caspases is a hallmark of apoptosis, which causes biochemical collapse of the
cell. Recent studies suggest that, rather than completely destroying a protein, caspase cleavage can confer novel characteristics
or functions. In this respect, the post-caspase role of Bcl-2 family proteins remains uncharacterized. Here, we showed that
Mcl-1, a pro-survival member of the Bcl-2 family, was cleaved by caspase-3 in non-small cell lung cancer (NSCLC) cells
undergoing chemotherapeutic agent-triggered apoptosis. Caspase cleavage partially impaired the anti-apoptotic activity of
Mcl-1 by reducing its mitochondrial localization and impeding its association with the permeability transition pore-forming
protein Bak. However, the stability of cleaved Mcl-1 was markedly enhanced because it was more refractory to ubiquitination-dependent proteasomal degradation, thereby improving cell viability to a greater extent than full-length Mcl-1 when
transiently expressed in NSCLC cells. These findings shed new light on the role of Mcl-1 in apoptosis and suggest potential
novel targets for optimizing the tumoricidal capacity of chemotherapy.