All ETDs from UAB

Advisory Committee Chair

Harald W Sontheimer

Advisory Committee Members

Louis B Nabors

Brian Sims

Anne Theibert

Jacques Wadiche

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

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 α-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 xc- transporter in glioma biology.

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