Peroxynitrite-induced mitochondrial translocation of PKCalpha causes U937 cell survival.
Our previous work has shown that non-toxic concentrations of peroxynitrite nevertheless commit U937 cells to mitochondrial permeability-transition (MPT)-dependent necrosis that is however prevented by a parallel survival signaling pathway involving cytosolic phospholipase A2 (cPLA2)-dependent arachidonic acid release and PKCalpha activation associated with the cytosolic translocation of Bad. The present study provides evidence of an early mitochondrial translocation of PKCalpha. Inhibition of the survival signaling at the level of either cPLA2, or PKC, was invariably associated with prevention of the mitochondrial localization of PKCalpha, with the mitochondrial translocation of Bad and Bax and with a very rapid lethal response. Collectively, the results presented in this study demonstrate that peroxynitrite, while committing U937 cells to necrosis, triggers a parallel signaling response leading to the cytosolic localization of two important members of the Bcl-2 family implicated in the onset of MPT.
Cerioni
Liana
L
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo Via S. Chiara, 27-61029 Urbino, PU, Italy.
Palomba
Letizia
L
Brüne
Bernhard
B
Cantoni
Orazio
O
D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000494:pharmacology / Q000502:physiology*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism*
C494819:BAD protein, human; C494826:BAX protein, human; D007211:Indoles; D008301:Maleimides; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D030421:Peroxynitrous Acid; D051571:Protein Kinase C-alpha; D010741:Phospholipases A; D054467:Phospholipases A2; C070515:bisindolylmaleimide I