title: ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis.
abstract: 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.
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, Jiangsu, People's Republic of China. qls1204@126.com.|Department of Neurosurgery, the Sixth People's Hospital of Yancheng, Yan-cheng, Jiangsu, People's Republic of China. qls1204@126.com.
authors.forename: Li-sen
authors.initials: LS
authors.lastname: Qin
authors.affiliation: Department of Neurosurgery, Shanghai Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China. 84518608@qq.com.
authors.forename: Pi-feng
authors.initials: PF
authors.lastname: Jia
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, 215021, China. zhiqing630@163.com.
authors.forename: Zhi-qing
authors.initials: ZQ
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, Jiangsu, People's Republic of China. qinlishen1204@163.com.
authors.forename: Shi-ming
authors.initials: SM
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D005910:Glioma / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D011714:Pyrans / Q000009:adverse effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000095662:Polyether Polyketides
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D011714:Pyrans; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C010327:salinomycin; D000095662:Polyether Polyketides