Cellular FLICE-inhibitory protein down-regulation contributes to celecoxib-induced apoptosis in human lung cancer cells
Cellular FLICE-inhibitory protein down-regulation contributes to celecoxib-induced apoptosis in human lung cancer cells
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DOI：
10.1158/0008-5472.can-06-2471
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发表时间：
2006-12-01
期刊：
影响因子：
11.2
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
--
作者：
Liu, Xiangguo;Yue, Ping;Sun, Shi-Yong
环氧化酶-2（考克斯-2）抑制剂塞来昔布是临床上批准用于结肠癌化学预防的药物，并已在各种临床试验中测试其化学预防和治疗功效。塞来昔布可诱导包括肺癌细胞在内的多种人类癌细胞凋亡。我们以前的工作表明，塞来昔布诱导死亡受体5的表达，导致诱导细胞凋亡和增强肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的人肺癌细胞凋亡。在本研究中，我们进一步表明，塞来昔布通过不依赖于考克斯-2的泛素/蛋白酶体依赖性机制下调人肺癌细胞中细胞FLICE抑制蛋白（c-FLIP）的表达，c-FLIP是死亡受体介导的外源性凋亡途径的主要负调节因子。过表达c-FLIP，特别是FLIPL，不仅抑制塞来昔布诱导的细胞凋亡，而且抑制塞来昔布和TRAIL联合诱导的细胞凋亡。因此，这些结果表明，c-FLIP下调也有助于塞来昔布诱导的细胞凋亡和增强TRAIL诱导的细胞凋亡，这补充了我们以前的发现，即外源性凋亡途径在塞来昔布诱导的人肺癌细胞凋亡中起着关键作用。总的来说，我们得出结论，塞来昔布诱导人肺癌细胞凋亡，通过激活外源性凋亡途径，主要是通过诱导死亡受体5和下调c-FLIP。
The cyclooxygenase-2 (COX-2) inhibitor celecoxib is an approved drug in the clinic for colon cancer chemoprevention and has been tested for its chemopreventive and therapeutic efficacy in various clinical trials. Celecoxib induces apoptosis in a variety of human cancer cells including lung cancer cells. Our previous work has shown that celecoxib induces death receptor 5 expression, resulting in induction of apoptosis and enhancement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. In the current study, we further show that celecoxib down-regulated the expression of cellular FLICE-inhibitory protein (c-FLIP), a major negative regulator of the death receptor-mediated extrinsic apoptotic pathway, through a ubiquitin/proteasome-dependent mechanism independent of COX-2 in human lung cancer cells. Overexpression of c-FLIP, particularly FLIPL, inhibited not only celecoxib-induced apoptosis but also apoptosis induced by the combination of celecoxib and TRAIL. These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-induced apoptosis and enhancement of TRAIL-induced apoptosis, which complements our previous finding that the extrinsic apoptotic pathway plays a critical role in celecoxib-induced apoptosis in human lung cancer cells. Collectively, we conclude that celecoxib induces apoptosis in human lung cancer cells through activation of the extrinsic apoptotic pathway, primarily by induction of death receptor 5 and down-regulation of c-FLIP.