Superoxide dismutase 1 (SOD1) is essential for H2O 2-mediated oxidation and inactivation of phosphatases in growth factor signaling

Jose C. Juarez, Mari Manuia, Mark E. Burnett, Oscar Betancourt, Benoit Boivin, David E. Shaw, Nicholas K. Tonks, Andrew P. Mazar, Fernando Doñate*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

163 Scopus citations

Abstract

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 H2O2, resulting in the protection of PTPs from H2O2-mediated oxidation. This, in turn, leads to the inhibition of EGF-, IGF-1-, and FGF-2-mediated phosphorylation of ERK1/2. Pretreatment with exogenous H2O 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 H2O 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.

Original languageEnglish (US)
Pages (from-to)7147-7152
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number20
DOIs
StatePublished - May 20 2008

Keywords

  • ATN-224
  • Angiogenesis
  • Cancer
  • Redox
  • Tetrathiomolybdate

ASJC Scopus subject areas

  • General

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