Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway

Abstract

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-b 1 , increased the expression of PKCd and PKCZ, 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 PKCb 1 by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCb 1 attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21 waf1/cip1 . Inhibition of PKCb 1 -mediated overexpression of p21 waf1/cip1 partially reduced the anti-apoptotic effect of PKCb 1 . The down-regulation of PKCb 1 provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCb 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.

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

“…The protein kinase C family has crucial regulatory roles in cell growth and cell-cycle progression (Frey et al, 1997;Ashton et al, 1999;Jiang et al, 2002;Deeds et al, 2003;Cerda et al, 2006). Various studies have shown that PKC suppression generally inhibits cell-cycle progression, whereas PKC activation stimulates cellcycle progression (Frey et al, 1997;Deeds et al, 2003;Cerda et al, 2006).…”

Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB

“…The proapoptotic effects of Cox-2 inhibitors are well documented (Sawaoka et al, 1998;Jiang et al, 2002). In non-small-cell lung cancer cell lines, genetic or pharmacological inhibition of Cox-2 enhances proteosomal degradation of the inhibitor of apoptosis survivin (Beltrami et al, 2004;Krysan et al, 2004a, b).…”

Cyclooxygenase-independent down-regulation of multidrug resistance–associated protein-1 expression by celecoxib in human lung cancer cells

“…For example, a COX-2-selective inhibitor celecoxib exerted synergistic antitumor effects when combined with gemcitaine or 5-fluorouracil in patients with advanced pancreatic cancer (2), and it enhanced the response to paclitaxel and carboplatin in early-stage non -small cell lung cancer (3). The mechanism underlying the antitumor activity of COX-2 inhibitors is thought to involve inhibition of COX-2 enzyme activity and induction of apoptosis, but it is unclear whether COX-2 inhibition is required to induce apoptosis (4).…”