Received for publication April 26, 2007.
Revised August 1, 2007.
Accepted for publication August 7, 2007.

CHOP-dependent DR5 induction and ubiquitin/proteasome-mediated c-FLIP downregulation contribute to enhancement of TRAIL-induced apoptosis by dimethyl-celecoxib in human non-small cell lung cancer cells

Abstract

2,5-dimethyl-celecoxib (DMC) is a derivative of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor with anticancer activity in both preclinical studies and clinical practice, and lacks COX-2-inhibitory activity. Several preclinical studies have demonstrated that DMC has better apoptosis-inducing activity than celecoxib, albeit with undefined mechanisms, and exhibits anticancer activity in animal models. In this study, we primarily investigated DMC's cooperative effect with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on induction of apoptosis and the underlying mechanisms in human non-small cell lung cancer (NSCLC) cells. We found that DMC was more potent than celecoxib in decreasing the survival and inducing apoptosis of NSCLC cells. When combined with TRAIL, DMC exerted enhanced or synergistic effects on induction of apoptosis, indicating that DMC cooperates with TRAIL to augment induction of apoptosis. To determine the underlying mechanism of the synergy between DMC and TRAIL, we have demonstrated that DMC induces a CHOP-dependent expression of DR5, a major TRAIL receptor, and reduces the levels of c-FLIP (both FLIP_L and FLIP_S), key inhibitors of death receptor-mediated apoptosis, by facilitating c-FLIP degradation through a ubiquitin /proteasome-dependent mechanism. Importantly, enforced expression of c-FLIP or silencing of DR5 expression using DR5 small interfering RNA abrogated the enhanced effects on induction of apoptosis by the combination of DMC and TRAIL, indicating that both DR5 upregulation and c-FLIP reduction contribute to cooperative induction of apoptosis by the combination of DMC and TRAIL. Collectively, we conclude that DMC sensitizes human NSCLC cells to TRAIL-induced apoptosis via induction of DR5 and downregulation of c-FLIP.

Key words: Mechanisms of cell killing/apoptosis, Membrane targets

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