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

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 ( angiogenesis ͉ cancer ͉ redox ͉ tetrathiomolybdate ͉ ATN-224

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

“…We have previously shown that LCS-1 can prevent serum-induced activation of the ERK and PI 3-kinase/AKT signaling pathways (6). In support of this, Juarez et al reported that ATN-224-mediated inhibition of SOD1 activity prevents growth factor-induced activation of ERK (18). The authors speculated that, when SOD1 activity is low, there is an abundant supply of reactive oxygen species that prevents the oxidation of tyrosine phosphates (18).…”

“…In support of this, Juarez et al reported that ATN-224-mediated inhibition of SOD1 activity prevents growth factor-induced activation of ERK (18). The authors speculated that, when SOD1 activity is low, there is an abundant supply of reactive oxygen species that prevents the oxidation of tyrosine phosphates (18). This causes the down-regulation of growth-promoting signals from tyrosine kinase receptors and this may be the mechanism by which ROS impair growth.…”

New Roles for Copper Metabolism in Cell Proliferation, Signaling, and Disease

“…This is an important challenge, as TTM, a potent Cu ϩ chelator, has been reported to be of therapeutic value in the treatment of several types of cancers as an anti-angiogenesis and anti-cancer molecule. Recently, ATN-224, an orally available choline salt derivative of TTM, has been suggested to preferentially target Cu,Zn-SOD in tumor and endothelial cells, with the implication that SOD1 plays a stimulatory role in growth factor signaling (45,46). SOD1 protects cells from oxidative stress and catalyzes the disproportionation of superoxide to hydrogen peroxide, molecules that have been established to play signaling roles in biology (47).…”

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

“…SODs are highly conserved metalloenzymes that use a Cu, Mn, Fe, or Ni cofactor to catalyze the conversion of superoxide anion to oxygen and hydrogen peroxide (27). Through this redox chemistry, SODs play important roles in antioxidant protection and in cell signaling processes involving reactive oxygen species (28)(29)(30). Curiously, the C. albicans genome contains an unusually large number of genes that encode SODs.…”