Activation of mitochondrial ERK protects cancer cells from death through inhibition of the permeability transition.
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.
Rasola
Andrea
A
Department of Biomedical Sciences, National Research Council Institute of Neuroscience and Venetian Institute of Molecular Medicine, University of Padua, 35121 Padua, Italy. andrea.rasola@unipd.it
Sciacovelli
Marco
M
Chiara
Federica
F
Pantic
Boris
B
Brusilow
William S
WS
Bernardi
Paolo
P
D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D048049:Extracellular Signal-Regulated MAP Kinases