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Nutr Cancer. 2008;60 Suppl 1:98-103. doi: 10.1080/01635580802381261.

NSAIDs downregulate Bcl-X(L) and dissociate BAX and Bcl-X(L) to induce apoptosis in colon cancer cells.

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University of Pittsburgh Cancer Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.


Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in preventing colorectal cancer. Apoptosis induction by NSAIDs plays a critical role in NSAID-mediated chemoprevention. Our previous study demonstrated that NSAIDs require the proapoptotic B-cell non-Hodgkin lymphoma-2 (Bcl-2) family member Bcl-2-associated x protein (BAX) to induce apoptosis and inhibit the expression of antiapoptotic basal cell lymphoma-extra large (Bcl-X(L)) in colon cancer cells. In this study, we further investigated how BAX and Bcl-X(L) mediate NSAID-induced apoptosis. We found that Bcl-X(L) is downregulated by NSAIDs in part through proteasome-mediated protein degradation. NSAIDs promote the dissociation of BAX and Bcl-X(L) and translocation of BAX to the mitochondria. Furthermore, we found that only wild-type BAX, but not a mutant BAX deficient in either protein-protein interaction or mitochondrial localization, was able to restore NSAID-induced apoptosis in the BAX-knockout colon cancer cells. These results suggest that NSAIDs induce apoptosis in colon cancer cells by dissociating BAX and Bcl-X(L), thereby promoting BAX mitochondrial translocation and multimerization.

[Indexed for MEDLINE]

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