Hypoxia Increases the Dependence of Glioma Cells on Glutathione

Toyin Adeyemi Ogunrinu,Harald Sontheimer

doi:10.1074/jbc.m110.161190

Toyin Adeyemi Ogunrinu, Harald Sontheimer

Open Access

https://doi.org/10.1074/jbc.m110.161190

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Abstract

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.

Highlights

Grants RO1 NS052634 and T32MH18882. □S The on-line version of this article contains supplemental Fig. 1. 1 To whom correspondence should be addressed: Dept. of Neurobiology, confers the specificity of this transport system
Sustained GSH synthesis becomes more critical for the support of glioma cell growth under hypoxic conditions compared with normoxic conditions
Previous studies show that changes in the oxygen tension within and around the tumor microenvironment lead to tumor hypoxia and modification of the redox status by paradoxically challenging tumor cells oxidatively and/or nitrosatively (15, 17, 18)

Summary

Introduction

Grants RO1 NS052634 and T32MH18882. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1. 1 To whom correspondence should be addressed: Dept. of Neurobiology, confers the specificity of this transport system. A Hypoxia-induced NO and ROS—Hypoxia has been shown to trypan blue exclusion assay demonstrated that cell viability was lead to increases in free radical production, notably ROS (17, unaffected under hypoxic and normoxic conditions (data not 18). If GSH production from L-cystine is required for cell response to hypoxic conditions as well as the effectiveness of its growth, supplementing the medium with GSHee alone would neutralization by GSH.

Results

Conclusion