The transient receptor potential (TRP) channel TRPM2 is an ion channel that modulates cell survival. We report here that full-length (TRPM2-L) and short (TRPM2-S) isoform expression was significantly increased in human neuroblastoma com-pared with adrenal gland. To differentiate the roles of TRPM2-L and TRPM2-S in cell proliferation and survival, we established neuroblas-toma SH-SY5Y cell lines stably expressing either TRPM2 isoform or empty vector. Cells expressing TRPM2-S showed significantly en-hanced proliferation, downregulation of phosphatase and tensin ho-molog (PTEN), and increased protein kinase B (Akt) phosphorylation and cell surface glucose transporter 1 (Glut1) compared with cells expressing TRPM2-L or empty vector. ERK phosphorylation was increased, and forkhead box O 3a (FOXO3a) levels were decreased. Inhibitor studies demonstrated that enhanced proliferation was depen-dent on phosphatidylinositol 3-kinase/Akt, ERK, and NADPH oxi-dase activation. On the other hand, TRPM2-S-expressing cells were significantly more susceptible to cell death induced by low H2O2 concentrations (50-100 μM), whereas TRPM2-L-expressing cells were protected. This was associated with a significant increase in FOXO3a, MnSOD (SOD2), and membrane Glut1 in TRPM2-L-expressing cells compared with TRPM2-S expressing cells. We con-clude that TRPM2 channels occupy a key role in cell proliferation and survival following oxidative stress in neuroblastoma. Our results suggest that overexpression of TRPM2-S results in increased prolif-eration through phosphatidylinositol 3-kinase/Akt and ERK path-ways, while overexpression of TRPM2-L confers protection against oxidative stress-induced cell death through FOXO3a and SOD. TRPM2 channels may represent a novel future therapeutic target in diseases involving oxidative stress.
All Science Journal Classification (ASJC) codes
- Cell Biology