Activation of System xc- Trafficking via an Akt-dependent Signal Transduction Pathway
Dr. Leah Chase, Hope College
System xc- is a heterodimeric plasma membrane transporter involved in the exchange of intracellular glutamate for extracellular cystine–a critical step in the production of the antioxidant glutathione. Previous studies in our lab have demonstrated that within ten minutes of exposure to H2O2, the percent of xCT protein localized to the plasma membrane of cells increases. The study described herein sought to establish a link between a putative “oxidative-stress activation” of Akt and trafficking of System xc-. To date, the role of Akt in mediating xCT trafficking has not been confirmed, due primarily to a lack of experimental replicates. Activation of Akt was seen in U138MG cells following ten-minute exposure to 3mM H2O2, and cells treated with the Akt inhibitor 10-DEBC (2.5µM) showed decreased phosphorylation of Akt at Ser473. Similar inhibition of Akt phosphorylation at Thr308 was observed following treatment of cells with 1.0µM API-2. Stimulation of cell cultures with H2O2 following one-hour exposure to 10-DEBC did not result in increased phosphorylation of Akt at Ser473, but similar treatment of cells with H2O2 following exposure to API-2 did show increased levels of phosphorylation at Thr308. These results indicate that 10-DEBC might be a more effective inhibitor of Akt activation in response to oxidative stress than API-2. Future experiments will seek to confirm the putative role of Akt in the activation of System xc- trafficking during periods of oxidative stress.
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