Abstract
Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used as immunosuppressive and chemotherapeutic agent. This study was undertaken to investigate the effects of DEX on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in cancer cells. We found that upregulation of c-FLIP(L) and downregulation of death receptor 5 (DR5; receptor for TRAIL ligand) contribute to the anti-apoptotic effect of DEX on TRAIL-induced apoptosis. DEX increased c-FLIP(L) expression at the transcriptional levels through the GSK-3β signaling pathway. The pharmacological inhibitor and catalytic mutant of GSK-3β suppressed DEX-induced upregulation of c-FLIP(L) expression. Furthermore, GSK-3β specific inhibitor markedly abolished DEX-mediated reduction of TRAIL-induced apoptosis in human renal cancer cells (Caki-1 and A498), human lung cancer cells (A549), and human breast cancer cells (MDA-MB361). In addition, DEX decreased protein stability of DR5 via GSK-3β-mediated upregulation of Cbl, an E3 ligase of DR5. Knockdown of Cbl by siRNA markedly inhibited DEX-induced DR5 downregulation. Taken together, these results suggest that DEX inhibits TRAIL-mediated apoptosis via GSK-3β-mediated DR5 downregulation and c-FLIP(L) upregulation in cancer cells.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential target for cancer therapy, owing to its ability to induce apoptosis of tumor cells without affecting noncancerous cells [1]
We examined whether DEX could interfere with anti-cancer drugs-induced apoptosis in human renal carcinoma cells
We focused whether DEX could interfere with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential target for cancer therapy, owing to its ability to induce apoptosis of tumor cells without affecting noncancerous cells [1]. TRAIL binds death receptors (DRs) and forms death-inducing signaling complexes (DISC) with adaptor proteins. DISC activate caspases, and induce apoptosis [2]. Downregulation of the death receptors (DRs) and pro-apoptotic proteins, and upregulation of the anti-apoptotic proteins, such as Bcl-2, Bcl-xL, and c-FLIP(L), leads to resistance to TRAIL-mediated apoptosis. Glucocorticoids (GCs) regulate multiple physiological processes and are involved in the development and maintenance of many tissues [3,4]. DEX downregulated amino acid carrier SLC7A5 expression and induced G1/S cell cycle arrest, autophagy, and apoptosis in BeWo choriocarcinoma cells [7]. DEX reduces cancer cell death by paclitaxel-treatment in breast carcinoma cells
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