Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

Rasola A; Sciacovelli M; Chiara FPantic BBrusilow WSBernardi P

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Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

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We studied human cancer cell models in which we detected constitutive activation of ERK. A fraction of active ERK was found to be located in mitochondria in RWPE-2 cells, obtained by v-Ki-Ras transformation of the epithelial prostate RWPE-1 cell line; in metastatic prostate cancer DU145 cells; and in osteosarcoma SAOS-2 cells. All these tumor cells displayed marked resistance to death caused by apoptotic stimuli like arachidonic acid and the BH3 mimetic EM20-25, which cause cell death through the mitochondrial permeability transition pore (PTP). PTP desensitization and the ensuing resistance to cell death induced by arachidonic acid or EM20-25 could be ablated by inhibiting ERK with the drug PD98059 or with a selective ERK activation inhibitor peptide. ERK inhibition enhanced glycogen synthase kinase-3 (GSK-3)-dependent phosphorylation of the pore regulator cyclophilin D, whereas GSK-3 inhibition protected from PTP opening. Neither active ERK in mitochondria nor pore desensitization was observed in non-transformed RWPE-1 cells. Thus, in tumor cells mitochondrial ERK activation desensitizes the PTP through a signaling axis that involves GSK-3 and cyclophilin D, a finding that provides a mechanistic basis for increased resistance to apoptosis of neoplastic cells.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第2期|726-731|共6页
作者
Rasola A; Sciacovelli M; Chiara FPantic BBrusilow WSBernardi P;
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作者单位

Department of Biomedical Sciences, National Research Council Institute of Neuroscience and Venetian Institute of Molecular Medicine, University of Padua,35121 Padua, Italy;

Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
glycogen synthase kinase-3; cyclophilin D; PTP; EM20-25; arachidonic acid;

Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition

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