Caspase cleavage of Mcl-1 impairs its anti-apoptotic activity and proteasomal degradation in non-small lung cancer cells
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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.
KeywordsMcl-1 Chemotherapy Lung cancer Bak Proteasomal degradation
Myeloid cell leukemia 1
Bcl-2-associated protein X
Non-small cell lung cancer
Poly ADP-ribose polymerase
Cell Counting Kit-8
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81472631 and 31200429).
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
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