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Abstract
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-XL) in colon cancer cells. In this study, we further investigated how BAX and Bcl-XL mediate NSAID-induced apoptosis. We found that Bcl-XL is downregulated by NSAIDs in part through proteasome-mediated protein degradation. NSAIDs promote the dissociation of BAX and Bcl-XL 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-XL, thereby promoting BAX mitochondrial translocation and multimerization.
ACKNOWLEDGMENTS
We thank our lab members for careful reading and comments on the article. This work is supported by National Institute of Health (NIH) Grant CA121105, CA106348, American Cancer Society Grant RSG-07-156-01-CNE (L. Zhang), Predoctoral Fellowships from NIH training Grant T32GM08424 and Department of Pharmacology (A. Bank), and grants from the Flight Attendant Medical Research Institute (FAMRI), the Alliance for Cancer Gene Therapy (ACGT) (J. Yu).
