Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells.
Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells.
复制标题
DOI：
--
复制
发表时间：
2001-09
期刊：
影响因子：
11.2
通讯作者：
Ying Huang;Qin He;M. J. Hillman;R. Rong;M. Sheikh
中科院分区：
文献类型：
--
作者：
Ying Huang;Qin He;M. J. Hillman;R. Rong;M. Sheikh
舒林酸是临床上研究最广泛的化学预防非类固醇抗炎药物。舒林酸硫化物是舒林酸的主要代谢产物之一，被认为通过诱导细胞凋亡来介导其抗肿瘤作用。最近的证据表明，舒林酸硫化物参与了涉及caspase 9和Bax的线粒体途径，以介导其凋亡效应[Zhang等人，Science(华盛顿。DC)，290：989-992,2000]。在这份报告中，我们证明了舒林酸硫化物也参与了膜死亡受体(DR)途径来介导细胞凋亡。在各种不同的结肠癌和前列腺癌细胞系中，舒林酸硫化物上调DR5并激活近端caspase8。硫化舒林酸特异性地上调DR5的水平，但不影响包括DR4、Fas和肿瘤坏死因子受体1在内的其他DR5的水平。为了进一步阐明DR5在硫化舒林酸诱导的细胞凋亡中的作用，我们使用了缺乏依赖Fas和肿瘤坏死因子受体1的凋亡反应但擅长介导依赖于DR5的凋亡的JCA-1前列腺癌细胞。将显性阴性的Fas相关死亡结构域稳定地导入JCA-1细胞，阻断内源性DR5诱导的细胞凋亡信号的流动，并研究了舒林酸硫化物诱导的细胞凋亡。我们的结果表明，通过阻断DR5依赖的凋亡通路，显性负Fas相关死亡结构域确实抑制了舒林酸硫化物诱导的细胞凋亡。此外，肿瘤坏死因子相关的凋亡诱导配体，即DR5的配体，也加强了硫化舒林酸诱导的所有细胞系的凋亡，从而进一步支持了DR5参与了硫化舒林酸诱导的细胞凋亡。因此，我们的结果表明，舒林酸硫化物也参与了涉及DR5和近端caspase8的膜DR途径，以诱导细胞凋亡。
Sulindac is the most extensively investigated clinically relevant chemopreventive nonsteroidal anti-inflammatory drug. Sulindac sulfide is one of the major metabolites of sulindac that is believed to mediate its antitumorigenic effects by inducing apoptosis. Recent evidence suggests that sulindac sulfide engages the mitochondrial pathway involving caspase 9 and Bax to mediate its apoptotic effects [Zhang et al., Science (Wash. DC), 290: 989-992, 2000]. In this report, we demonstrate that sulindac sulfide also engaged the membrane death receptor (DR) pathway to mediate apoptosis. Sulindac sulfide up-regulated DR5 and activated the proximal caspase 8 in various different colon and prostate cancer cell lines. Sulindac sulfide specifically up-regulated the DR5 levels but had no effect on the levels of other DRs including DR4, Fas, and tumor necrosis factor receptor 1. To further delineate the role of DR5 in sulindac sulfide-induced apoptosis, we used JCA-1 prostate cancer cells that are deficient in mounting a Fas and tumor necrosis factor receptor 1-dependent apoptotic response but are proficient in mediating DR5-dependent apoptosis. JCA-1 cells were stably transfected with dominant-negative Fas-associated death domain to block the flow of apoptotic signals originating from the endogenous DR5, and sulindac sulfide-induced apoptosis was investigated. Our results indicated that by blocking the DR5-dependent apoptotic pathway, dominant-negative Fas-associated death domain did indeed inhibit sulindac sulfide-induced apoptosis. Furthermore, exogenous tumor necrosis factor-related apoptosis-inducing ligand, the ligand for DR5, also potentiated sulindac sulfide-induced apoptosis in all of the cell lines tested, thereby further supporting the involvement of DR5 in sulindac sulfide-induced apoptosis. Thus, our results demonstrate that sulindac sulfide also engages the membrane DR pathway involving DR5 and proximal caspase 8 to induce apoptosis.