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

Abstract

Diabetes mellitus is a complex and heterogeneous disease, which has -cell dysfunction at its core. Glucotoxicity affects pancreatic islets, causing -cell apoptosis. However, the role of JNK/-catenin signaling in glucotoxic -cell apoptosis is not well understood. Recently, we identified tetraspanin-2 (TSPAN2) protein as a proapoptotic -cell factor induced by glucose, suggesting that TSPAN2 might contribute to pancreatic -cell glucotoxicity. To investigate the effects of glucose concentration on TSPAN2 expression and apoptosis, we used reverted immortalized RNAKT-15 human pancreatic cells. High TSPAN2 levels up-regulated phosphorylated (p) JNK and induced apoptosis. p-JNK enhanced the phosphorylation of -catenin and Dickkopf-1 (Dkk1). Dkk1 knockdown by small interfering (si)RNA up-regulated nuclear -catenin, suggesting that it is a JNK/-catenin-dependent pathway. siRNA-mediated TSPAN2 depletion in RNAKT-15 cells increased nuclear -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 cells, thereby promoting the apoptosis of RNAKT-15 cells by regulating the JNK/-catenin pathway in response to high glucose concentrations. Targeting TSPAN2 could be a potential therapeutic strategy to treat glucose toxicity-induced -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/-catenin signaling pathway in human pancreatic cells.