Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway
Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β1-dependent pathway
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DOI：
10.1038/sj.onc.1205778
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发表时间：
2002-09-05
期刊：
影响因子：
8
通讯作者：
Wong, BCY
中科院分区：
文献类型：
--
作者：
Jiang, XH;Lam, SK;Wong, BCY
非甾体抗炎药（NSAID）可降低胃肠道癌症的风险。最近，特异性环氧合酶-2（考克斯-2）抑制剂也显示出类似的保护作用。然而，特定考克斯-2抑制剂抗增殖作用的确切机制仍未完全清楚，并且这些保护作用是否主要通过抑制考克斯-2活性和前列腺素合成来介导仍然存在争议。鉴定由考克斯-2抑制剂调节的分子靶点可以更好地理解其促凋亡和抗肿瘤活性。本研究探讨了考克斯-2特异性抑制剂SC-236对胃癌的作用及其可能的分子靶点。我们发现SC-236诱导胃癌细胞凋亡。然而，这种作用不依赖于考克斯-2抑制。SC-236下调AGS细胞中PKC-β（1）的蛋白表达和激酶活性，增加PKC δ和PKCeta的表达，但不改变其他PKC亚型的表达。此外，外源性野牡丹素或PGE（2）受体拮抗剂不能逆转SC-236对PKC β（1）的抑制作用，这表明这种作用是通过一种不依赖于环氧合酶活性和前列腺素合成的机制发生的。PKC β（1）的过表达减弱了AGS细胞对SC-236的凋亡反应，并与p21（wafl/cip 1）的过表达相关。抑制PKQ 1介导的p21（wafl/cip 1）过表达部分降低了PKC β的抗凋亡作用（1）。PKC β（1）的下调为特异性考克斯-2抑制剂在培养的胃癌细胞中的COX非依赖性凋亡效应提供了解释。PKC β（1）在胃癌中起生存调节作用，考克斯-2抑制剂SC-236下调PKC β（1）的表达可能为胃癌的治疗提供新的靶点。
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(wafl/cip1). Inhibition of PKQ1-mediated overexpression of p21(wafl/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.