Selenite suppresses hydrogen peroxide-induced cell apoptosis through inhibition of ASK1/JNK and activation of PI3-K/Akt pathways.

Abstract

The relationship between selenium and signal molecules has not been well elucidated. It was found that physiological concentration of selenite, <3 <mu>M, reduced ASK1 activity and induced PI3-kinase (PI3-K)/Akt pathways in HT1080 cells. Duration of these signal molecules by selenite was much longer than that by growth factors and other stresses. The longer duration time of these signal molecules may be important to maintain normal functions against stresses. Selenite increased cell proliferation through up-regulation of Bcl-2 expression, mitochondrial membrane potential, adenosine triphosphate (ATP) generation, and glucose uptake mediated by PI3-K pathway. High concentration of H(2)O(2) increased an apoptotic signal molecule, ASK1, which resulted in Bcl-2 down-regulation, membrane potential disruption, decreased ATP and glucose uptake, and activation of caspases. However, an antiapoptotic signal molecule, Akt, was activated also by H(2)O(2), but duration of its activation was much shorter. Selenite blocked apoptosis induced by H(2)O(2), which was related to blocking ASK1 and further stimulating PI3-kinase/Akt activities. Selenite blocked mitochondrial membrane potential disruption by 400 muM H(2)O(2). Selenite also blocked caspase-9 and -3 activities and apoptosis induced by 500 muM H(2)O(2), even after mitochondrial membrane potential disruption. These observations demonstrate that selenite increases cell proliferation and maintains cell survival by activating the antiapoptotic signal and blocking the apoptotic signal.