Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antineoplastic Agents / pharmacology*
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Calcium-Binding Proteins / metabolism
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Cytoskeletal Proteins / antagonists & inhibitors*
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Cytoskeletal Proteins / metabolism
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Diclofenac / pharmacology*
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Down-Regulation
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism*
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Membrane Glycoproteins / metabolism
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NF-kappa B / metabolism*
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Nerve Tissue Proteins / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Synaptotagmin I
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Synaptotagmins
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / metabolism
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Transcription, Genetic / drug effects
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Tumor Cells, Cultured
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Wnt Proteins
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beta Catenin
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antineoplastic Agents
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CTNNB1 protein, human
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Calcium-Binding Proteins
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Cytoskeletal Proteins
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Intercellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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NF-kappa B
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Nerve Tissue Proteins
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Synaptotagmin I
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Trans-Activators
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Wnt Proteins
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beta Catenin
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Synaptotagmins
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Diclofenac