Journal of Experimental & Clinical Cancer Research 2015-01-01

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

Li-sen Qin, Pi-feng Jia, Zhi-qing Zhang, Shi-ming Zhang

Index: J. Exp. Clin. Cancer Res 34 , 57, (2015)

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Abstract

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.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.Thus, salinomycin mainly induces programmed necrosis in cultured glioma cells.