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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.