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Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3

¹ The University of Texas Health Science Center; ² The University of Texas, M. D. Anderson Cancer Center, Houston, Texas; and ³ National Health Research Institutes, Zhunan, Taiwan

Requests for reprints: Kenneth K. Wu, National Health Research Institutes, 35 Keyan Road, Zhunan Township, Miaoli County 350, Taiwan. Phone: 886-37-583042; Fax: 886-37-586402; E-mail: kkgo{at}nhri.org.tw.

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 14-3-3 protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3 proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 µmol/L inhibited 14-3-3 protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3 promoter activity. As 14-3-3 promoter activation is mediated by peroxisome proliferator–activated receptor (PPAR), we determined the correlation between 14-3-3 inhibition and PPAR suppression by NSAIDs. Sulindac sulfide inhibited PPAR protein expression and PPAR transcriptional activity. Overexpression of PPAR by adenoviral transfer rescued 14-3-3 proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3 suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPAR transduction. Stable expression of 14-3-3 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 PPAR/14-3-3 transcriptional pathway. These results suggest that 14-3-3 is a target for the prevention and therapy of colorectal cancer. [Cancer Res 2007;67(7):3185–91]

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