CCAAT/Enhancer Binding Protein Homologous Protein-Dependent Death Receptor 5 Induction and Ubiquitin/Proteasome-Mediated Cellular FLICE-Inhibitory Protein Down-Regulation Contribute to Enhancement of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Dimethyl-Celecoxib in Human Non–Small-Cell Lung Cancer Cells

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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 the 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 the induction of apoptosis, indicating that DMC cooperates with TRAIL to augment the induction of apoptosis. To determine the underlying mechanism of the synergy between DMC and TRAIL, we have demonstrated that DMC induces a CCAAT/enhancer binding protein homologous protein-dependent expression of DR5, a major TRAIL receptor, and reduces the levels of cellular FLICE-inhibitory protein (c-FLIP) (both the long and short forms), key inhibitors of death receptor-mediated apoptosis, by facilitating c-FLIP degradation through a ubiquitin/proteasome-dependent mechanism. It is noteworthy that 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 up-regulation and c-FLIP reduction contribute to cooperative induction of apoptosis by the combination of DMC and TRAIL. Together, we conclude that DMC sensitizes human NSCLC cells to TRAIL-induced apoptosis via induction of DR5 and down-regulation of c-FLIP.