Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon.
To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3epsilon protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 mumol/L inhibited 14-3-3epsilon protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3epsilon promoter activity. As 14-3-3epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPARdelta), we determined the correlation between 14-3-3epsilon inhibition and PPARdelta suppression by NSAIDs. Sulindac sulfide inhibited PPARdelta protein expression and PPARdelta transcriptional activity. Overexpression of PPARdelta by adenoviral transfer rescued 14-3-3epsilon proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3epsilon suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARdelta transduction. Stable expression of 14-3-3epsilon in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARdelta/14-3-3epsilon transcriptional pathway. These results suggest that 14-3-3epsilon is a target for the prevention and therapy of colorectal cancer.
Liou
Jun-Yang
JY
University of Texas Health Science Center, M. D. Anderson Cancer Center, Houston, Texas, USA.
Ghelani
Dipak
D
Yeh
Sam
S
Wu
Kenneth K
KK
D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000378:metabolism; D000096926:Benzenesulfonamides
D048948:14-3-3 Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D007213:Indomethacin; D047494:PPAR delta; D011720:Pyrazoles; D013449:Sulfonamides; D013467:Sulindac; D051025:bcl-Associated Death Protein; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C494819:BAD protein, human; C482983:YWHAE protein, human; C025462:sulindac sulfide; C025463:sulindac sulfone