ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis

Background: the primary glioblastoma multiforme (gbm) is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. the search for novel and more efficient chemo-agents against this disease is urgent. salinomycin induces broad anti-cancer effects; however,its role in gbm and the underlying mechanism are not clear. results: here we found that salinomycin induced both apoptosis and necrosis in cultured glioma cells,and necrosis played a major role in contributing salinomycin's cytotoxicity. salinomycin induced p53 translocation to mitochondria,where it formed a complex with cyclophilin-d (cypd). this complexation was required for mitochondrial permeability transition pore (mptp) opening and subsequent programmed necrosis. blockade of cyp-d by sirna-mediated depletion or pharmacological inhibitors (cyclosporin a and sanglifehrin a) significantly suppressed salinomycin-induced glioma cell necrosis. meanwhile,p53 stable knockdown alleviated salinomycin-induced necrosis in glioma cells. reactive oxygen species (ros) production was required for salinomycin-induced p53 mitochondrial translocation,mptp opening and necrosis,and anti-oxidants n-acetylcysteine (nac) and pyrrolidine dithiocarbamate (pdtc) inhibited p53 translocation,mptp opening and glioma cell death. conclusions: thus,salinomycin mainly induces programmed necrosis in cultured glioma cells. © 2015 qin et al.