TY - JOUR T1 - Distinct Effects of Different Calcium-Mobilizing Agents on Cell Death in NG108-15 Neuroblastoma X Glioma Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 486 LP - 494 DO - 10.1124/mol.61.3.486 VL - 61 IS - 3 AU - Ting-Yu Chin AU - Hsiou-Min Hwang AU - Sheau-Huei Chueh Y1 - 2002/03/01 UR - http://molpharm.aspetjournals.org/content/61/3/486.abstract N2 - The effects of different calcium-mobilizing agents on cell death were characterized in NG108-15 neuroblastoma x glioma hybrid cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) increased the cytosolic Ca2+ concentration ([Ca2+]i) and caused cell death. Thapsigargin (TG) not only increased the [Ca2+]i and caused cell death but also induced neurite outgrowth via activation of phospholipase A2 and cytochrome P450 epoxygenase. In contrast, bradykinin increased the [Ca2+]i, but had no effect on cell morphology or cell death. Cell death occurred by two different mechanisms, one of which was caspase-3–dependent and the other caspase-3–independent. Caspase-3 activation was Ca2+-dependent, whereas neurite outgrowth was Ca2+-independent. TG- or FCCP-induced caspase-3 activation occurred at the same time, but the cell death induced by TG was delayed. TG treatment did not enhance the generation of nitric oxide or cAMP or secretion of glial-derived neurotrophic factor or neurotrophin-3, but activated sphingosine kinase. Furthermore, inhibition of sphingosine kinase accelerated TG-induced cell death, and exogenous sphingosine 1-phosphate (S1P) protected cells from FCCP-induced cell death by about 60%. These results indicate that, in these cells, depletion of intracellular nonmitochondrial or mitochondrial Ca2+ stores causes cell death, that TG activates phospholipase A2 and sphingosine kinase, and that arachidonic acid induces neurite outgrowth, whereas S1P delays cell death. ER -