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 Ca2+ 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.

Computational Approaches for Identification of Potential Plant Bioactives as Novel G6PD Inhibitors Using Advanced Tools and Databases

“…In vitro analysis has revealed that Staurosporine induces apoptosis in many cell lines [ 52 ]. In the apoptosis of cancer cells, various signaling pathways have been involved, including mitogen-activated protein kinase (MAPK), cyclooxygenase-2 (COX-2), Janus kinase (JAK), phosphatidylinositol 3-kinase (PI3K), signal transducer and activator of transcription (STAT3) and endoplasmic reticulum stress [ 53 , 54 , 55 , 56 , 57 , 58 , 59 ].…”

An In Vitro Evaluation of Biochemical Processes Involved in Lead‐Induced Changes on Ram Spermatozoa

“…The effect of staurosporine on the acrosomal membrane stability may be explained because this PKC inhibitor can enhance COX‐2 expression (Saeki et al. ), and thus enable the destabilization process of membrane by the prostaglandin A (PGA) pathway.…”

Staurosporine suppresses survival of HepG2 cancer cells through Omi/HtrA2-mediated inhibition of PI3K/Akt signaling pathway

“…Many signaling pathways have been reported to be involved in staurosporine-induced cell death or apoptosis of cancer cells, including cyclooxygenase-2 (COX-2) pathway, 16 mitogen-activated protein kinase (MAPK) pathway, 17,18 Janus kinase (JAK)/(signal transducer and activator of transcription) STAT3 pathway, 19 endoplasmic reticulum (ER) stress, 20 and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. 21,22 Although a number of studies have evidenced that suppression of PI3K/Akt pathway may be functionally linked to the process of cell death induced by staurosporine, 23,24 the detailed mechanism underlying inhibition of PI3K/Akt signaling pathway remains largely unclear.…”