Amino-acid Transport and the Biology of Human Gliomas

University Of Alabama At Birmingham, Birmingham AL

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Abstract

Glutamate is the major excitatory neurotransmitter in the human brain and is indispensable for normal neuronal signaling. However, under conditions of energy failure, for example following pound stroke, uncontrolled release of glutamate can cause "excitotoxic" death of neurons. Glutamate toxicity may be more commonly associated with diseases of the nervous system. Indeed, recent studies surprisingly demonstrated that astrocyte-derived primary brain tumors (gliomas) release large quantities of glutamate into the pcritumoral space and led to the hypothesis that this glutamate release may purposely kill neurons thereby vacating space for invading tumor cells. In this proposal we are pursuing an alternate hypothesis. We hypothesize that glutamate release from glioma cells is an obligatory byproduct of cystine uptake into glioma cells via system Xc, a cystine-glutamate exchanger. Cystine uptake is essential for the production of glutathione (GSH) to maintain the cells redox status. Impairment of cystine uptake depletes GSH leading to growth] arrest due to loss of defense against reactive oxygen species. Furthermore, glutamate released in the processj not only causes excitotoxic pertiumoral neuronal loss but causes the autocrine/paracrine activation of AMPAj receptors that promote glioma cell invasion. This proposal seeks to characterize the glutamate] release/cystine uptake pathway(s) utilized byglioma cells with the objective to suppress tumor growth and] invasion by inhibiting these transporters. The proposed studies range from a cellular and molecular1 identification of the underlying amino acid transporters and their role in tumor biolcgy to the pruclinicalj evaluation of drugs that specificallyinterfere with these transporters in animal models of the disease. j