NSAIDs downregulate Bcl-X(L) and dissociate BAX and Bcl-X(L) to induce apoptosis in colon cancer cells.
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.
Bank
Alexander
A
University of Pittsburgh Cancer Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Yu
Jian
J
Zhang
Lin
L
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D046988:Proteasome Endopeptidase Complex