Overexpression of protein kinase C-β1 isoenzyme suppresses indomethacin-induced apoptosis in gastric epithelial cells

Abstract

Background and Aims: We have previously reported that nonsteroidal anti- inflammatory drugs (NSAIDs) could induce apoptosis of gastric epithelial cells both in vivo and in vitro. This study investigated the role of protein kinase C (PKC) isoforms in the regulation of NSAID-induced apoptosis. Methods: Protein levels of 12 PKC isoforms in AGS cells, in the presence or absence of indomethacin, were determined by western blot. The effect of PKC- β1 overexpression by transfection with its complementary DNA (cDNA) on indomethacin-induced apoptosis and apoptosis-related genes, including p53, p21(waf1/cip1), and c-myc, was further investigated. Results: Treatment with indomethacin decreased the abundance of PKC-β1 and increased that of PKCβ2, η, and ε, but did not alter the expression of PKC α, γ, ζ, δ, ι, and μ. Overexpression of PKC-β1 attenuated the apoptotic response of AGS cells to indomethacin, associated with overexpression of p21(waf1/cip1) in both messenger RNA and protein levels. Inhibition of PKC-β1-mediated overexpression of p21(waf1/cip1) by its antisense cDNA partially reduced the antiapoptotic effect of PKC-β1. Conclusions: Indomethacin-induced apoptosis in gastric cancer cells is partly mediated by differential regulation of PKC isoform expression. Enhanced expression of exogenous PKC-β1 protects against indomethacin-induced apoptosis through up-regulation of p21(waf1/cip1).