Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/ß-catenin signaling pathway in human pancreatic ß cells.

Diabetes mellitus is a complex and heterogeneous disease, which has ß-cell dysfunction at its core. Glucotoxicity affects pancreatic islets, causing ß-cell apoptosis. However, the role of JNK/ß-catenin signaling in glucotoxic ß-cell apoptosis is not well understood. Recently, we identified tetraspanin-2 (TSPAN2) protein as a proapoptotic ß-cell factor induced by glucose, suggesting that TSPAN2 might contribute to pancreatic ß-cell glucotoxicity. To investigate the effects of glucose concentration on TSPAN2 expression and apoptosis, we used reverted immortalized RNAKT-15 human pancreatic ß cells. High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p-JNK enhanced the phosphorylation of ß-catenin and Dickkopf-1 (Dkk1). Dkk1 knockdown by small interfering (si)RNA up-regulated nuclear ß-catenin, suggesting that it is a JNK/ß-catenin-dependent pathway. siRNA-mediated TSPAN2 depletion in RNAKT-15 cells increased nuclear ß-catenin. This decreased BCL2-associated X protein (Bax) activation, leading to marked protection against high glucose-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Thus, TSPAN2 might have induced Bax translocation and caspase-3 activation in pancreatic ß cells, thereby promoting the apoptosis of RNAKT-15 cells by regulating the JNK/ß-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-induced ß-cell failure.-Hwang, I.-H., Park, J., Kim, J. M., Kim, S. I., Choi, J.-S., Lee, K.-B., Yun, S. H., Lee, M.-G., Park, S. J., Jang, I.-S. Tetraspanin-2 promotes glucotoxic apoptosis by regulating the JNK/ß-catenin signaling pathway in human pancreatic ß cells.