Hypoxia increases the dependence of glioma cells on glutathione.
Glutathione (GSH) is an essential antioxidant responsible for the maintenance of intracellular redox homeostasis. As tumors outgrow their blood supply and become hypoxic, their redox homeostasis is challenged by the production of nitric oxide and reactive oxygen species (ROS). In gliomas, the sustained import of L-cystine via the L-cystine/L-glutamate exchanger, system x(c)(-), is rate-limiting for the synthesis of GSH. We show that hypoxia causes a significant increase in NO and ROS but without affecting glioma cell growth. This is explained by a concomitant increase in the utilization of GSH, which is accompanied by an increase in the cell-surface expression of xCT, the catalytic subunit of system x(c)(-), and L-cystine uptake. Growth was inhibited when GSH synthesis was blocked by buthionine sulfoximine (BSO), an inhibitor of the enzyme required for GSH synthesis, or when cells were deprived of L-cystine. These findings suggest that glioma cells show an increased requirement for GSH to maintain growth under hypoxic conditions. Therefore, approaches that limit GSH synthesis such as blocking system x(c)(-) may be considered as an adjuvant to radiation or chemotherapy.
Ogunrinu
Toyin Adeyemi
TA
Department of Neurobiology and Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0021, USA.
Sontheimer
Harald
H
D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
D027182:Amino Acid Transport System y+; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D009569:Nitric Oxide; D005978:Glutathione