Role of the cystine/glutamate exchanger in glioma cell biology

Changes in the glioma microenvironment including oxygen (O2) levels, supply of amino acid such as L-glutamate and L-cystine and glutathione (GSH) concentrations play a critical role in glioma biology. Previous data from our laboratory and others have implicated the L-cystine/L-glutamate exchanger, system xc - in the invasion and proliferation of cancers including glioma. The central aim of this dissertation was to characterize the contribution of L-cystine uptake, GSH synthesis and L-glutamate release to migration and proliferation of glioma cells. In my first study, I examined the role of system xc- mediated L-glutamate release on glioma migration. I show that activation of Ca2+ permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-Rs) induces intracellular Ca2+ oscillations which promote migration. These findings suggest that a primary role of L-glutamate release in glioma cells is to promote migration through the autocrine and paracrine activation of Ca2+ permeable AMPA-Rs. In my second study, I examined how hypoxia affects the dependency of glioma growth on L-cystine and GSH. I show that glioma cells respond to hypoxia with increases in free radical production. When D54-MG cells were propagated under hypoxic conditions, we observed an increase in surface expression of xCT alone. I also show that hypoxia increases system xc- sensitive L-cystine uptake and consumption rates of GSH. In my last study, I examined the expression profile of xCT across high grade human glioma cell lines and in biopsied glioma samples from over 30 patients. The results show a heterogeneous expression of xCT ranging from no expression to abundant expression. Interestingly, glioma cells with minimal xCT expression no longer depend on L-cystine or GSH for growth. These studies show multiple important roles for the system x c- transporter in glioma biology.