title: Staurosporine synergistically potentiates the deoxycholate-mediated induction of COX-2 expression.
abstract: Colorectal cancer is a major cause of cancer-related death in western countries, and thus there is an urgent need to elucidate the mechanism of colorectal tumorigenesis. A diet that is rich in fat increases the risk of colorectal tumorigenesis. Bile acids, which are secreted in response to the ingestion of fat, have been shown to increase the risk of colorectal tumors. The expression of cyclooxygenase (COX)-2, an inducible isozyme of cyclooxygenase, is induced by bile acids and correlates with the incidence and progression of cancers. In this study, we investigated the signal transduction pathways involved in the bile-acid-mediated induction of COX-2 expression. We found that staurosporine (sts), a potent protein kinase C (PKC) inhibitor, synergistically potentiated the deoxycholate-mediated induction of COX-2 expression. Sts did not increase the stabilization of COX-2 mRNA. The sts- and deoxycholate-mediated synergistic induction of COX-2 expression was suppressed by a membrane-permeable Ca(2+) chelator, a phosphoinositide 3-kinase inhibitor, a nuclear factor-κB pathway inhibitor, and inhibitors of canonical and stress-inducible mitogen-activated protein kinase pathways. Inhibition was also observed using PKC inhibitors, suggesting the involvement of certain PKC isozymes (η, θ, ι, ζ, or μ). Our results indicate that sts exerts its potentiating effects via the phosphorylation of p38. However, the effects of anisomycin did not mimic those of sts, indicating that although p38 activation is required, it does not enhance deoxycholate-induced COX-2 expression. We conclude that staurosporine synergistically enhances deoxycholate-induced COX-2 expression in RCM-1 colon cancer cells.
authors.affiliation: Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Saeki
authors.affiliation: Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Inui
authors.affiliation: Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Saya
authors.initials: S
authors.lastname: Fujioka
authors.affiliation: Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Nomura
authors.affiliation: Laboratory of Food Science, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory of Food Science, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: Laboratory of Food Science, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sato
authors.affiliation: Laboratory of Molecular Nutrition, Kyoto Prefectural University, Kyoto, Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Kanamoto
keywords: Bile acids; colorectal cancer cells; cyclooxygenase‐2; staurosporine