Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling.
Superoxide dismutase 1 (SOD1) is an abundant copper/zinc enzyme found in the cytoplasm that converts superoxide into hydrogen peroxide and molecular oxygen. Tetrathiomolybdate (ATN-224) has been recently identified as an inhibitor of SOD1 that attenuates FGF-2- and VEGF-mediated phosphorylation of ERK1/2 in endothelial cells. However, the mechanism for this inhibition was not elucidated. Growth factor (GF) signaling elicits an increase in reactive oxygen species (ROS), which inactivates protein tyrosine phosphatases (PTP) by oxidizing an essential cysteine residue in the active site. ATN-224-mediated inhibition of SOD1 in tumor and endothelial cells prevents the formation of sufficiently high levels of H(2)O(2), resulting in the protection of PTPs from H(2)O(2)-mediated oxidation. This, in turn, leads to the inhibition of EGF-, IGF-1-, and FGF-2-mediated phosphorylation of ERK1/2. Pretreatment with exogenous H(2)O(2) or with the phosphatase inhibitor vanadate abrogates the inhibition of ERK1/2 phosphorylation induced by ATN-224 or SOD1 siRNA treatments. Furthermore, ATN-224-mediated SOD1 inhibition causes the down-regulation of the PDGF receptor. SOD1 inhibition also increases the steady-state levels of superoxide, which induces protein oxidation in A431 cells but, surprisingly, does not oxidize phosphatases. Thus, SOD1 inhibition in A431 tumor cells results in both prooxidant effects caused by the increase in the levels of superoxide and antioxidant effects caused by lowering the levels of H(2)O(2). These results identify SOD1 as a master regulator of GF signaling and as a therapeutic target for the inhibition of angiogenesis and tumor growth.
Juarez
Jose C
JC
Attenuon, LLC, San Diego, CA 92121, USA.
Manuia
Mari
M
Burnett
Mark E
ME
Betancourt
Oscar
O
Boivin
Benoit
B
Shaw
David E
DE
Tonks
Nicholas K
NK
Mazar
Andrew P
AP
Doñate
Fernando
F
D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D008982:Molybdenum / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000502:physiology*; D000072105:Superoxide Dismutase-1
D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D008982:Molybdenum; C020809:tetrathiomolybdate; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D010744:Phosphoric Monoester Hydrolases; D010100:Oxygen