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

Li-sen Qin1,2, Pi-feng Jia3, Zhi-qing Zhang4

  • 1Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, Jiangsu, People's Republic of China. qls1204@126.com.

Journal of Experimental & Clinical Cancer Research : CR
|May 31, 2015
PubMed
Abstract

Insights

Salinomycin triggers programmed necrosis in glioma cells, a key mechanism for its anti-cancer effects. This involves p53 translocation to mitochondria and reactive oxygen species production, offering new therapeutic avenues for glioblastoma multiforme.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
  • Novel chemotherapeutic agents are urgently needed for GBM treatment.
  • Salinomycin exhibits anti-cancer properties, but its mechanism in GBM is unclear.

Purpose of the Study:

  • To investigate the role and mechanism of salinomycin in glioblastoma multiforme (GBM).
  • To elucidate the cell death pathways induced by salinomycin in glioma cells.

Main Methods:

  • Cell culture of glioma cells.
  • Assessment of apoptosis and necrosis.
  • Analysis of p53 translocation to mitochondria.
  • Mitochondrial permeability transition pore (mPTP) opening assays.
  • Silencing of cyclophilin-D (CyPD) using siRNA.
  • Pharmacological inhibition of mPTP.
  • p53 knockdown studies.
  • Reactive oxygen species (ROS) detection and inhibition.

Main Results:

  • Salinomycin induced both apoptosis and necrosis in glioma cells, with necrosis being predominant.
  • Salinomycin promoted p53 translocation to mitochondria, forming a complex with CyPD, leading to mPTP opening and programmed necrosis.
  • Inhibition of CyPD or p53, or scavenging of ROS, significantly suppressed salinomycin-induced necrosis.
  • ROS production was essential for salinomycin-induced p53 mitochondrial translocation and necrosis.

Conclusions:

  • Salinomycin primarily induces programmed necrosis in cultured glioma cells.
  • The p53-CyPD-mPTP pathway, modulated by ROS, is crucial for salinomycin's cytotoxic effect in GBM.

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