Diclofenac attenuates Wnt/beta-catenin signaling in colon cancer cells by activation of NF-kappaB.
The dysregulation of Wnt/beta-catenin signaling and subsequent upregulation of beta-catenin response transcription (CRT) occur frequently in colon cancer cells. Non-steroidal anti-inflammatory drugs (NSAIDs) can repress CRT in colorectal cancer, but little is known about the mechanism of action. We show that the NSAID diclofenac inhibits Wnt/beta-catenin signaling without altering the level of beta-catenin protein and reduces the expression of beta-catenin/TCF-dependent genes. Diclofenac induced the degradation of IkappaBalpha, which increased free nuclear factor kappaB (NF-kappaB) in cells. Also, the ectopic expression of p65, which is a component of NF-kappaB, suppressed CRT. Our findings suggest that diclofenac inhibits Wnt/beta-catenin signaling via the activation of NF-kappaB in colon cancer cells.
Cho
Munju
M
PharmcoGenomic Research Center, Inje University, Busan 633-165, Republic of Korea.
Gwak
Jungsug
J
Park
Seoyoung
S
Won
Jaejoon
J
Kim
Dong-Eun
DE
Yea
Sung Su
SS
Cha
In-June
IJ
Kim
Tae Kook
TK
Shin
Jae-Gook
JG
Oh
Sangtaek
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004008:Diclofenac / Q000494:pharmacology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D050863:Synaptotagmin I; D050857:Synaptotagmins; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D050863:Synaptotagmin I; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D050857:Synaptotagmins; D004008:Diclofenac