Mitochondrial c-Jun NH2-terminal kinase prevents the accumulation of reactive oxygen species and reduces necrotic damage in neural tumor cells that lack trophic support.
In response to different stress signals, the c-Jun NH(2)-terminal kinase (JNK) can trigger cell death. However, JNK also facilitates the survival and cell cycle progression of tumor cells by mechanisms that are poorly defined. Here, we show that schwannoma RN22 cells can survive and proliferate under serum-free conditions although serum withdrawal rapidly induces mitochondrial fission and swelling. Although the morphologic changes observed in the mitochondria did not trigger cytochrome c release, they were accompanied by an increase in the mitochondrial membrane potential (DeltaPsi(M)) and of immunoreactivity for active JNK in these organelles. Pharmacologic inhibition of JNK provoked a further increase of the DeltaPsi(M), an increase in reactive oxygen species (ROS) production, and a sustained decrease in cell viability due to necrosis. This increase in necrosis was prevented by the presence of ROS scavengers. Immunoreactivity for active JNK was also observed in the mitochondria of neuroblastoma 1E-115 and neuroblastoma 2a neuroblastoma cell lines on serum withdrawal, whereas active JNK was barely detected in serum-deprived fibroblasts. Accordingly, the reduction in neural tumor cell viability induced by JNK inhibition was largely attenuated in serum-deprived fibroblasts. These data indicate that local activation of JNK in the mitochondria can protect against necrotic cell death associated with ROS production, facilitating the growth of neural tumor cells subjected to serum deprivation.
López-Sánchez
Noelia
N
Department of developmental Neurobiology, Consejo Superior de Investigaciones Cientificas, Avda Doctor Arce 37, E-28002 Madrid, Spain.
Rodríguez
José-Rodrigo
JR
Frade
José María
JM
D000818:Animals; D016923:Cell Death; D016895:Culture Media, Serum-Free; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009336:Necrosis; D009442:Neurilemmoma / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases