The involvement of reactive oxygen species derived from NADPH oxidase-1 activation on the constitutive tyrosine auto-phosphorylation of RET proteins.
Reactive oxygen species (ROS) play a key role in neoplastic growth and tumor invasion is supported by various experimental data. In this study, we analyzed the participation of ROS in the RET tyrosine auto-phosphorylation. The NIH3T3 cell lines transfected with cRET, MEN2A, and MEN2B individually (designated NIH3T3cRET, NIH3T3 RET-MEN2A, and NIH3T3RET-MEN2B) showed the elevated levels of intracellular ROS, and concomitantly increased Rac1 expression, as well as down-regulation of Mn SOD and Cu/Zn SOD in comparison with the parental cell line expressing RET. H₂O₂ enhanced the constitutive tyrosine auto-phosphorylation of RET-MEN2A and RET-MEN2B proteins, and this increase was attenuated by treatment with the NOX inhibitor diphenyliodonium (DPI) or catalase. We also showed that DPI inhibited dimerization of RET-MEN2A. Elevated ROS derived from NOX1 activation and downregulation of SOD in NIH3T3RET-MEN2A and NIH3T3RET-MEN 2B cells may be involved in RET constitutive tyrosine auto-phosphorylation, and scavengers of ROS such as catalase and blocking NOX1 are useful for targeting RET tyrosine kinase activation in cancer.
Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University , Aichi , Japan.
S
S
Qiao
K
K
Fan
T
T
Iwashita
M
M
Ichihara
M
M
Yoshino
M
M
Takahashi
D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases