Celecoxib inhibits the expression of survivin via the suppression of promoter activity in human colon cancer cells.
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.
Sakoguchi-Okada
Naoko
N
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Takahashi-Yanaga
Fumi
F
Fukada
Kazuhiro
K
Shiraishi
Fumie
F
Taba
Yoji
Y
Miwa
Yoshikazu
Y
Morimoto
Sachio
S
Iida
Mitsuo
M
Sasaguri
Toshiyuki
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000068579:Celecoxib; D003110:Colonic Neoplasms / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D000077022:Survivin; D051820:TCF Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D000077022:Survivin; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D000068579:Celecoxib