ROS-p53-cyclophilin-D Signaling Mediates Salinomycin-induced Glioma Cell Necrosis

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2015 May 31

PMID 26024660

Citations 54

Authors

Li-Sen Qin

Pi-Feng Jia

Zhi-Qing Zhang

Shi-Ming Zhang

Affiliations

Soon will be listed here.

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.

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References

Cho S, Woo S, Ko S . Butein suppresses breast cancer growth by reducing a production of intracellular reactive oxygen species. J Exp Clin Cancer Res. 2014; 33:51. PMC: 4064524. DOI: 10.1186/1756-9966-33-51. View

Naujokat C, Steinhart R . Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012; 2012:950658. PMC: 3516046. DOI: 10.1155/2012/950658. View

Wang Y, Jiang T . Understanding high grade glioma: molecular mechanism, therapy and comprehensive management. Cancer Lett. 2013; 331(2):139-46. DOI: 10.1016/j.canlet.2012.12.024. View

Fuchs D, Daniel V, Sadeghi M, Opelz G, Naujokat C . Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells. Biochem Biophys Res Commun. 2010; 394(4):1098-104. DOI: 10.1016/j.bbrc.2010.03.138. View

Pollack I . Neuro-oncology: Therapeutic benefits of reirradiation for recurrent brain tumors. Nat Rev Neurol. 2010; 6(10):533-5. DOI: 10.1038/nrneurol.2010.144. View

Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H . Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature. 2005; 434(7033):652-8. DOI: 10.1038/nature03317. View

Zhou S, Wang F, Wong E, Fonkem E, Hsieh T, Wu J . Salinomycin: a novel anti-cancer agent with known anti-coccidial activities. Curr Med Chem. 2013; 20(33):4095-101. PMC: 4102832. DOI: 10.2174/15672050113109990199. View

Riccioni R, Dupuis M, Bernabei M, Petrucci E, Pasquini L, Mariani G . The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Blood Cells Mol Dis. 2010; 45(1):86-92. DOI: 10.1016/j.bcmd.2010.03.008. View

Mao J, Fan S, Ma W, Fan P, Wang B, Zhang J . Roles of Wnt/β-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis. 2014; 5:e1039. PMC: 4040703. DOI: 10.1038/cddis.2013.515. View

10.

Qiu Y, Yu T, Wang W, Pan K, Shi D, Sun H . Curcumin-induced melanoma cell death is associated with mitochondrial permeability transition pore (mPTP) opening. Biochem Biophys Res Commun. 2014; 448(1):15-21. DOI: 10.1016/j.bbrc.2014.04.024. View

11.

Lu J, Shi Z, Xu H . The mitochondrial cyclophilin D/p53 complexation mediates doxorubicin-induced non-apoptotic death of A549 lung cancer cells. Mol Cell Biochem. 2013; 389(1-2):17-24. DOI: 10.1007/s11010-013-1922-1. View

12.

Clarke S, McStay G, Halestrap A . Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A. J Biol Chem. 2002; 277(38):34793-9. DOI: 10.1074/jbc.M202191200. View

13.

Zhen Y, Wang G, Zhu L, Tan S, Zhang F, Zhou X . P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol. 2014; 229(10):1475-83. DOI: 10.1002/jcp.24589. View

14.

Cassidy L, Barry P, Shaw C, Duffy J, Kennedy S . Platelet derived growth factor and fibroblast growth factor basic levels in the vitreous of patients with vitreoretinal disorders. Br J Ophthalmol. 1998; 82(2):181-5. PMC: 1722477. DOI: 10.1136/bjo.82.2.181. View

15.

Basso E, Fante L, Fowlkes J, Petronilli V, Forte M, Bernardi P . Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem. 2005; 280(19):18558-61. DOI: 10.1074/jbc.C500089200. View

16.

Jangamreddy J, Ghavami S, Grabarek J, Kratz G, Wiechec E, Fredriksson B . Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells. Biochim Biophys Acta. 2013; 1833(9):2057-69. DOI: 10.1016/j.bbamcr.2013.04.011. View

17.

Wang Q, Li P, Li A, Jiang W, Wang H, Wang J . Plasma specific miRNAs as predictive biomarkers for diagnosis and prognosis of glioma. J Exp Clin Cancer Res. 2012; 31:97. PMC: 3554474. DOI: 10.1186/1756-9966-31-97. View

18.

Khasraw M, Lassman A . Neuro-oncology: late neurocognitive decline after radiotherapy for low-grade glioma. Nat Rev Neurol. 2009; 5(12):646-7. DOI: 10.1038/nrneurol.2009.194. View

19.

Javadov S, Kuznetsov A . Mitochondrial permeability transition and cell death: the role of cyclophilin d. Front Physiol. 2013; 4:76. PMC: 3622878. DOI: 10.3389/fphys.2013.00076. View

20.

Zhou J, Li P, Xue X, He S, Kuang Y, Zhao H . Salinomycin induces apoptosis in cisplatin-resistant colorectal cancer cells by accumulation of reactive oxygen species. Toxicol Lett. 2013; 222(2):139-45. DOI: 10.1016/j.toxlet.2013.07.022. View