Nonsteroidal anti-inflammatory drugs (
NSAIDs) reduce the risk of
gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific
COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and
prostaglandin synthesis. Identification of molecular targets regulated by
COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor
SC-236 on
gastric cancer. We showed that
SC-236 induced apoptosis in
gastric cancer cells. However, this effect was not dependent on COX-2 inhibition.
SC-236 down-regulated the
protein expression and
kinase activity of PKC-beta(1), increased the expression of PKCdelta and PKCeta, but did not alter the expression of other PKC
isoforms in AGS cells. Moreover, exogenous
prostaglandins or
PGE(2) receptor antagonists could not reverse the inhibition effect on PKCbeta(1) by
SC-236, which suggested that this effect occurred through a mechanism independent of
cyclo-oxygenase activity and
prostaglandin synthesis. Overexpression of PKCbeta(1) attenuated the apoptotic response of AGS cells to
SC-236 and was associated with overexpression of p21(waf1/cip1). Inhibition of PKCbeta(1)-mediated overexpression of p21(waf1/cip1) partially reduced the anti-apoptotic effect of PKCbeta(1). The down-regulation of PKCbeta(1) provides an explanation for COX-independent apoptotic effects of specific
COX-2 inhibitor in cultured
gastric cancer cells. We also suggest that PKCbeta(1) act as survival mediator in
gastric cancer, and its down-regulation by
COX-2 inhibitor SC-236 may provide new target for future treatment of
gastric cancer.