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

Rasola, Andrea, Sciacovelli, Marco, Chiara, Federica, Pantic, Boris, Brusilow, William S., Bernardi, Paolo
Proceedings of the National Academy of Sciences of the United States of America 2010 v.107 no.2 pp. 726-731
apoptosis, arachidonic acid, cyclophilins, death, drugs, epithelium, glycogen (starch) synthase, humans, metastasis, mitochondria, mitogen-activated protein kinase, models, neoplasm cells, osteosarcoma, permeability, phosphorylation, prostatic neoplasms
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.