Calcium-independent Phospholipase A2 (iPLA2β)-mediated Ceramide Generation Plays a Key Role in the Cross-talk between the Endoplasmic Reticulum (ER) and Mitochondria during ER Stress-induced Insulin-secreting Cell Apoptosis

摘要: Endoplasmic reticulum (ER) stress induces INS-1 cell apoptosis by a pathway involving Ca2+-independent phospholipase A2 (iPLA2β)-mediated ceramide generation, but the mechanism which iPLA2β and ceramides contribute to is not well understood. We report here that both caspase-12 caspase-3 are activated in cells following induction of ER with thapsigargin, only cleavage amplified overexpressing (OE), relative empty vector-transfected cells, suppressed inhibition. also led release cytochrome c Smac and, unexpectedly, their accumulation cytosol OE cells. These findings raise likelihood participates stress-induced activating intrinsic apoptotic pathway. Consistent this possibility, we find promotes mitochondria, opening mitochondrial permeability transition pore, loss membrane potential (ΔΨ) these changes greater generation mitochondria fractions Exposure alone ΔΨ forskolin. dysfunction inhibited forskolin, as inactivation or NSMase, suggesting iPLA2β-mediated via sphingomyelin hydrolysis during affect mitochondria. In support, inhibition NSMase prevents release. Collectively, our indicate iPLA2β-ceramide axis plays critical role insulin-secreting stress.