Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Chemoprevention of gastric cancer through modulation of Protein Kinase C by non-steroidal anti-inflammatory drugs

CY Wong, XH Jiang, GH Zhu, MCM Lin, HF Kung, SK Lam

Department of Medicine, and Institute of Molecular Biology, University of Hong Kong, Hong Kong

AIM: We have demonstrated that aspirin, indomethacin and specific cyclooxygenase-2 inhibitors induced apoptosis in gastric cancer cells, which is the molecular basis of the chemopreventive effect observed in epidemiological studies. We further investigate the role of protein kinase C (PKC) signaling in NSAID-induced apoptosis of gastric cancer. METHODS: Gastric cancer cell line AGS with wild type p53 and its PKC-beta-1 and -2 transfected derivatives were treated with various concentrations of protein kinase C inhibitors (Ro-31-8220 and chelerythrine), non-steroidal anti-inflammatory drug (indomethacin), and specific cyclooxygenase-2 inhibitor (SC-236). Apoptosis was measured by acridine orange staining and FACS analysis. Changes in apoptosis-related oncogenes were determined by western blotting. RESULTS: PKC inhibitors arrested cells at G0/G1 phase and induced apoptosis, with overexpression of p53, p21, c-myc and bax. 12-0-tetradecanoyl-phorbol 13-acetate (TPA), which activated PKC, inhibited indomethacin-induced apoptosis and upregulated p21 expression. Indomethacin or SC-236 treatment decreased PKC-beta-1 expression. Overexpression of PKC-beta-1 could both inhibit indomethacin- or SC-236-induced apoptosis and upregulate p21 expression. Inhibition of this upregulation of p21 by its antisense oligonucleotides partially reduced the anti-apoptotic effect of PKC-beta-1. CONCLUSIONS: Indomethacin- or COX-2 inhibitor-induced apoptosis in gastric cancer is partly mediated by differential expression of PKC isoenzyme expression. Enhanced expression of PKC-beta-1 protects against indomethacin-induced apoptosis through upregulation of p21. We are currently investigating the relationship between PKC isoenzymes and p21.

KEY WORDS: protein kinase C, COX-2 inhibitors, apoptosis, gastric cancer.

For more information, contact

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on chemotherapy.