Celecoxib inhibits the expression of survivin via the suppression of promoter activity in human colon cancer cells.

Abstract

We investigated the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on human colon cancer cell lines to clarify the mechanisms underlying the chemopreventive effect of NSAIDs. Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, induced apoptosis and strongly reduced the expression of an anti-apoptotic protein, survivin, in both protein and mRNA levels in HCT-116 cells. Subsequently, we conducted luciferase reporter assay using a reporter gene driven by the human survivin promoter. A series of analyses using luciferase reporter constructs containing fragments of the survivin promoter and electrophoretic mobility shift assay indicated that the -75/-66 bp region relative to the initiating codon was involved in celecoxib action to suppress survivin promoter activity. Celecoxib also suppressed the activity of TOPflash, T-cell factor reporter plasmid, and the reporter gene driven by the human cyclin D1 promoter, suggesting that this compound inhibited the expression of Wnt/beta-catenin signaling target genes. Further, we found that other NSAIDs including indomethacin, resveratrol, and SC-560 induced apoptosis and suppressed the expression of survivin and the Wnt/beta-catenin signaling pathway in HCT-116 cells, indicating that these effects were likely to be common among NSAIDs. Moreover, NSAIDs (celecoxib, SC-560 and indomethacin) also suppressed the expression of cyclin D1 and survivin on other colon cancer cell lines (DLD-1 and SW-620). Our results suggested that NSAIDs could inhibit proliferation and induce apoptosis in colon cancer cells by inhibition of survivin expression and the Wnt/beta-catenin signaling pathway.

• Authors: Naoko Sakoguchi-Okada, Fumi Takahashi-Yanaga, Kazuhiro Fukada, Fumie Shiraishi, Yoji Taba, Yoshikazu Miwa, Sachio Morimoto, Mitsuo Iida, Toshiyuki Sasaguri
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 73 Issue 9 Pg. 1318-29 (May 01 2007) ISSN: 0006-2952 [Print] England
• PMID: 17270149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Pyrazoles
• RNA, Messenger
• Sulfonamides
• Survivin
• TCF Transcription Factors
• Wnt Proteins
• beta Catenin
• Cyclin D1
• Celecoxib

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Celecoxib
• Colonic Neoplasms (pathology)
• Cyclin D1 (metabolism)
• Gene Expression (drug effects)
• Humans
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Promoter Regions, Genetic (drug effects)
• Pyrazoles (pharmacology)
• RNA, Messenger (metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Survivin
• TCF Transcription Factors (metabolism)
• Tumor Cells, Cultured
• Wnt Proteins (metabolism)
• beta Catenin (genetics, metabolism)