¹Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong

²Department of Gastroenterology, Rui-jin Hospital, Shanghai, PR China

³Institute of Molecular Biology, The University of Hong Kong, Hong Kong

⁴Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA

Correspondence to: BCY Wong, E-mail: bcywong@hku.hk

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-₁, increased the expression of PKC and PKC, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE₂ receptor antagonists could not reverse the inhibition effect on PKC₁ by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKC₁ attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21^waf1/cip1. Inhibition of PKC₁-mediated overexpression of p21^waf1/cip1 partially reduced the anti-apoptotic effect of PKC₁. The down-regulation of PKC₁ provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKC₁ 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.

Oncogene (2002) 21, 6113-6122. doi:10.1038/sj.onc.1205778

gastric cancer; apoptosis; protein kinase C; cyclo-oxygenase-2; cancer prevention

NSAIDs, nonsteroidal antiinflammatory drugs; COX, cyclooxygenase; PKC, protein kinase C; TPA, 12-0-tetradecanoylphorbol-13-acetate; FBS, fetal bovine serum; NF-B, nuclear factor-B; PPAR, peroxisome proliferator activated receptors