Non-steroidal anti-inflammatory drug-induced apoptosis in gastric cancer cells is blocked by protein kinase C activation through inhibition of c-myc

Abstract

Summary Apoptosis plays a major role in gastrointestinal epithelial cell turnover, ulcerogenesis and tumorigenesis. We have examined apoptosis induction by non-steroidal anti-inflammatory drugs (NSAIDs) in human gastric (AGS) cancer cells and the role of protein kinase C (PKC) and apoptosis-related oncogenes. After treatment with aspirin or indomethacin, cell growth was quantified by MTT assay, and apoptosis was determined by acridine orange staining, DNA fragmentation and flow cytometry. The mRNA and protein of p53, p21 waf1/cip1 and c-myc was detected by Northern and Western blotting respectively. The influence of PKC on indomethacin-induced apoptosis was determined by co-incubation of 12-O-tetradecanoylphorbol 13-acetate (TPA). The role of c-myc was determined using its antisense oligonucleotides. The results showed that both aspirin and indomethacin inhibited cell growth and induced apoptosis of AGS cells in a dose-and time-dependent manner, without altering the cell cycle. Indomethacin increased c-myc mRNA and protein, whereas p53 and p21 waf1/cip1 were unchanged. Down-regulation of c-myc by its antisense oligonucleotides reduced apoptosis induction by indomethacin. TPA could inhibit indomethacininduced apoptosis and accumulate cells in G 2 /M. Overexpression of c-myc was inhibited by TPA and p21 waf1/cip1 mRNA increased. In conclusion, NSAIDs induce apoptosis in gastric cancer cells which may be mediated by up-regulation of c-myc proto-oncogene. PKC activation can abrogate the effects of NSAIDs by decreasing c-myc expression.

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

“…Another group demonstrated that a PKCb inhibitor exhibited anti-angiogenic and anti-tumor effects in human gastric cancer xenografts (Teicher et al, 2001b). Previously, our group have reported that PKC inhibitors induced apoptosis in human gastric cancer cell lines through modulating apoptosis-related genes (Zhu et al, 1999a) and activation of PKC by the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) inhibited the apoptosis induced by indomethacin in gastric cancer cells, accompanied by the upregulation of expression of p21 waf1/cip1 and downregulation of c-myc (Zhu et al, 1999b). Besides, we also demonstrated that overexpression of PKCb 1 suppressed indomethacin-induced apoptosis in gastric cancer cells through the up-regulation of p21 waf1/cip1 (Zhu et al, 2000).…”

Effect of celecoxib on E-cadherin, VEGF, microvessel density and apoptosis in gastric cancer

“…11 However, most in vitro studies have shown that induction of apoptosis by NSAIDs and selective COX-2 inhibitors is COX-2 dependent. 8,[12][13][14][15][16][17] Inhibition of angiogenesis also plays a role in the chemoprevention of COX-inhibitors. Expression of COX-2 is found to be associated with VEGF expression and microvessel density (MVD) in gastric cancer, [18][19][20][21] and NSAIDs were found to inhibit in vitro angiogenesis of human microvascular endothelial cells.…”

Therapeutic mechanism of ginkgo biloba exocarp polysaccharides on gastric cancer

“…Like apoptosis, proliferation and differentiation are regulated by genes. C-myc is an important gene involved in the control of cell proliferation, and could up-regulate cell cycle progression, and induce cell proliferation [26][27][28][29] . C-fos gene is considered as an early response gene, and its expression level was in proportion to the differentiation degree of gastric cancer [30][31][32] .…”