ScholarWorks@중앙대학교

초록

Background Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells; however, many malignancies, including human bladder cancer, develop resistance to TRAIL, thereby limiting its therapeutic potential. 5-Aminoimidazole-4-carboxamide riboside (AICAR), an AMP-activated protein kinase (AMPK) activator, has been reported to inhibit cancer cell growth and overcome TRAIL resistance, although its role in bladder cancer remains poorly defined. Objective This study aimed to determine whether AICAR could sensitize TRAIL-resistant human bladder cancer T24 cells to TRAIL-mediated apoptosis and to elucidate the underlying molecular mechanisms. Methods T24 cells were treated with AICAR and/or TRAIL, and cell viability and apoptosis were assessed. Expression of apoptosis-related proteins, mitochondrial dysfunction, and activation of mitogen-activated protein kinase (MAPK) signaling were evaluated using biochemical and molecular analyses. Results Combined treatment with AICAR and TRAIL significantly decreased cell viability and markedly increased apoptotic cell death compared with either treatment alone. These effects were accompanied by upregulation of death receptor 5 and Bax, Bid truncation, downregulation of Bcl-2, and cytochrome c release associated with mitochondrial membrane destabilization. Furthermore, co-treatment markedly enhanced phosphorylation of p38 MAPK. Inhibition of p38 MAPK using a p38 MAPK-selective inhibitor attenuated apoptosis induction and restored cell viability, indicating a critical role for this pathway. Conclusions These findings demonstrate that AICAR sensitizes T24 cells to TRAIL-mediated apoptosis through activation of activation of p38 MAPK. This combination strategy may therefore represent a promising approach for overcoming TRAIL resistance in human bladder cancer.

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