PKCδ-mediated regulation of FLIP expression in human colon cancer cells

✍ Scribed by Qingding Wang; Xiaofu Wang; Yuning Zhou; B. Mark Evers

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: French
• Weight: 530 KB
• Volume: 118
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.21373

✦ Synopsis

FLICE-like inhibitory protein (FLIP), a naturally occurring caspase-inhibitory protein that lacks the critical cysteine domain necessary for catalytic activity, is a negative regulator of Fas-induced apoptosis. Decreased FLIP levels sensitize tumor cells to Fas-and TRAIL-mediated apoptosis; however, the cellular mechanisms regulating FLIP expression have not been defined. Here, we examined the roles of the PKC and NF-jB pathway in the regulation of FLIP in human colon cancers. FLIP mRNA levels were increased in Caco-2 cells by treatment with PMA; actinomycin D completely inhibited the induction of FLIP by PMA, indicating transcriptional regulation. PKC inhibitors G€ o6983 and Ro-31-8220 blocked PMA-stimulated FLIP expression. Pretreatment with the PKCdselective inhibitor rottlerin or transfection with PKCd siRNA inhibited PMA-induced FLIP expression, which identifies a role for PKCd in FLIP induction. Treatment with the proteasome inhibitor, MG132, or the NF-jB inhibitor (e.g., PDTC and gliotoxin), or overexpression of the superrepressor of IjB-a inhibited PMA-induced upregulation of FLIP. Moreover, PMA-induced NF-jB transactivation was blocked by GF109203x. In conclusion, our results demonstrate a critical role for PKCd/NF-jB in the regulation of FLIP in human colon cancer cells.