Cell Surface Expression Of xCT Is Regulated By The Akt Signaling Pathway
(Meeting Abstract Supplement) 1017.10
System xc– is a heterodimeric plasma membrane transporter, comprised of xCT and CD98, which plays a critical role in the maintenance of intracellular glutathione levels. We have previously demonstrated that the cell surface expression of xCT increases by nearly 2-fold within 10 min of exposure of confluent U-138MG human glioma cells to H2O2. In addition, we have shown that cell surface expression of xCT is higher in non-confluent U138MG cultures than confluent cultures. In this study, we sought to determine if the Akt signaling pathway regulates xCT cell surface expression during oxidative stress and cell proliferation, since Akt activation is associated with H2O2 exposure and cell proliferation in other cell types. In support of this hypothesis, we observed a significant increase in Akt phosphorylation in non-confluent U138MG cells compared to confluent cultures and in confluent cells following a ten-minute exposure to H2O2 compared to vehicle-treated confluent cells. Inhibition of Akt signaling with an Akt inhibitor cocktail or transfection with a dominant-negative mutant of Akt prevented the H2O2-mediated trafficking of xCT to the membrane in confluent U138MG cells and decreased basal xCT membrane expression in non-confluent cultures to those observed in confluent cultures. Thus, these data suggests that the cell surface expression of xCT is ultimately regulated by activation of the Akt signaling pathway.