Hydrogen peroxide attenuates the prosurvival signaling of insulin-like growth factor-1 through two pathways.
Although it has been well established that oxidative stress triggering a variety of signaling pathways leads to cell death, little attention has been paid to how these pathways affect prosurvival factors such as insulin-like growth factor-1 (IGF-1). In this study, we found that the prosurvival signaling of IGF-1 was attenuated by H₂O₂. To study the mechanism underlying this phenomenon, cells pretreated with Trolox or various glutamate receptor antagonists [i.e. N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801), non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), metabolic glutamate receptor antagonists LY341495 and CPCCOEt] were exposed to H₂O₂, and then stimulated by IGF-1. The phosphorylation statuses of IGF-1 receptors, Akt and ERK, were determined by western blotting, and cell viability was analyzed by an MTT assay. IGF-1 exerted a potent neuroprotective effect against B27 deprivation, and this effect was abolished by 100 μM H₂O₂. Meanwhile, the phosphorylation of IGF-1 receptors, Akt and ERK, was attenuated. Moreover, the phosphorylation of Akt was more susceptible to H₂O₂ insult than IGF-1 receptors. MK-801 increased the phosphorylation of IGF-1 receptors and its downstream target Akt, and thereby promoted cell survival, whereas the other glutamate receptor antagonists exerted no effect. Antioxidant Trolox did not restore IGF-1 signaling, but it increased Akt phosphorylation and also increased cell viability. These results showed that H₂O₂ impaired IGF-1 prosurvival signaling through two pathways. One pathway disrupted the autophosphorylation of IGF-1 receptors through NMDA receptors and the other directly dephosphorylated Akt.
Department of Neuropharmacology, School of Pharmaceutical Sciences, Sun-Yat-sen University, Guangzhou, China.
Chengming
C
Sun
Dejun
D
Wang
Wenhua
W
Zheng
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt