Celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 expression via GADD153/CHOP
Celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 expression via GADD153/CHOP
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DOI：
10.1038/sj.onc.1210894
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发表时间：
2008-04-01
期刊：
影响因子：
8
通讯作者：
Sheikh, M. S.
中科院分区：
文献类型：
--
作者：
He, Q.;Luo, X.;Sheikh, M. S.
环氧合酶-2（考克斯-2）抑制剂是一种很有前途的抗癌药物，但长期高剂量使用会导致不良心血管事件。考克斯-2抑制剂的抗癌或毒性心血管作用的分子机制仍不清楚。在这里，我们报告了考克斯-2选择性塞来昔布和一种新的考克斯-2抑制剂ON 09310上调死亡受体5（DR 5），并与肿瘤坏死因子相关凋亡诱导配体（TRAIL），DR 5的配体，诱导凋亡考克斯-2阳性和阴性癌细胞。我们还表明，这两种药物参与GADD 153/CHOP转录上调DR 5的表达，GADD 153/CHOP是一个C/EBP同源转录因子参与细胞应激反应和凋亡。基于我们的研究结果，我们提出：（1）这些药物似乎至少部分通过使GADD 153/CHOP激活DR 5依赖性凋亡途径来介导其作用;（2）它们对GADD 153/CHOP和DR 5表达的调节似乎独立于其COX 2抑制作用。我们的研究结果还表明，ON 09310通常比塞来昔布更有效，并且在较低浓度下，与TRAIL强烈合作以诱导细胞凋亡。综上所述，我们的研究结果形成了未来深入研究的基础，以进一步探索TRAIL和/或激动性抗DR 5抗体与低剂量考克斯-2抑制剂组合作为癌症预防和治疗的合理方法的效用。
Cyclooxygenase-2 (COX-2) inhibitors are promising anticancer agents but their long-term use at high doses is associated with adverse cardiovascular events. The molecular mechanisms underlying the anticancer or toxic cardiovascular effects of COX-2 inhibitors remain unknown. Here we report that COX-2-selective celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 (DR5) and cooperate with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the ligand for DR5, to induce apoptosis in COX-2-positive and -negative cancer cells. We also show that both agents engage GADD153/CHOP to transcriptionally upregulate DR5 expression; GADD153/CHOP is a C/EBP homologous transcription factor implicated in cellular stress response and apoptosis. Based on our results, we propose that (1) these agents appear to mediate their effects, at least in part, by engaging GADD153/CHOP to activate DR5-dependent apoptotic pathway and (2) their regulation of GADD153/CHOP and DR5 expression appears to occur independent of their COX2 inhibitory effects. Our results also indicate that ON09310 is generally more potent than celecoxib and, at lower concentration, strongly cooperates with TRAIL to induce apoptosis. Taken together, our findings form the basis for future in-depth studies to further explore the utility of TRAIL and/or agonistic anti-DR5 antibodies in combination with low-dose COX-2 inhibitors as a rational approach for cancer prevention and treatment.