The aim of the present study is to elucidate the signaling pathway involved in death of human neuroblastoma SK-N-SH cells induced by Naja naja atra phospholipase A2 (PLA2). Upon exposure to PLA2, p38 MAPK activation, ERK inactivation, ROS generation, increase in intracellular Ca2+ concentration, and upregulation of Fas and FasL were found in SK-N-SH cells. SB202190 (p38MAPK inhibitor) suppressed upregulation of Fas and FasL. N-Acetylcysteine (ROS scavenger) and BAPTA-AM (Ca2+ chelator) abrogated p38 MAPK activation and upregulation of Fas and FasL expression, but restored phosphorylation of ERK. Activated ERK was found to attenuate p38 MAPK-mediated upregulation of Fas and FasL. Deprivation of catalytic activity could not diminish PLA2-induced cell death and Fas/FasL upregulation. Moreover, the cytotoxicity of arachidonic acid and lysophosphatidylcholine was not related to the expression of Fas and FasL. Taken together, our results indicate that PLA2-induced cell death is, in part, elicited by upregulation of Fas and FasL, which is regulated by Ca 2+- and ROS- evoked p38 MAPK activation, and suggest that non-catalytic PLA2 plays a role for the signaling pathway. J. Cell. Biochem. 106: 93-102, 2009.
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