Cellular FLICE-Inhibitory Protein Down-regulation Contributes to Celecoxib-Induced Apoptosis in Human Lung Cancer Cells

Xiangguo Liu,Axel H SchöNthal,Ping Yue,Shi-Yong Sun,Fadlo R Khuri

doi:10.1158/0008-5472.can-06-2471

Xiangguo Liu, Axel H SchöNthal + Show 3 more

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https://doi.org/10.1158/0008-5472.can-06-2471

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Abstract

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 FLIP(L), 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.

Highlights

Celecoxib, a marketed anti-inflammatory and anti-pain drug, is being tested in clinical trials for its chemopreventive and therapeutic effects against a broad spectrum of epithelial malignancies, including lung cancers, either as a single agent or in combination with other agents
We show for the first time that celecoxib, in addition to up-regulating death receptor 5, down-regulates cellular FLICEinhibitory protein (c-FLIP) expression, which contributes to celecoxib-induced apoptosis in non–small-cell lung cancer cells
Because c-FLIP levels are modulated by many cancer therapeutic agents, we were interested in determining whether celecoxib altered c-FLIP expression levels

Summary

Introduction

A marketed anti-inflammatory and anti-pain drug, is being tested in clinical trials for its chemopreventive and therapeutic effects against a broad spectrum of epithelial malignancies, including lung cancers, either as a single agent or in combination with other agents. Our previous results have shown that celecoxib induces apoptosis in non–small-cell lung cancer cell lines primarily through the activation of the extrinsic death receptor pathway [4]. We show for the first time that celecoxib, in addition to up-regulating death receptor 5, down-regulates c-FLIP expression, which contributes to celecoxib-induced apoptosis in non–small-cell lung cancer cells.

Results

Conclusion