Hypoxia Increases the Dependence of Glioma Cells on Glutathione
Hypoxia Increases the Dependence of Glioma Cells on Glutathione
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DOI：
10.1074/jbc.m110.161190
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发表时间：
2010-11-26
影响因子：
4.8
通讯作者：
Sontheimer, Harald
中科院分区：
文献类型：
--
作者：
Ogunrinu, Toyin Adeyemi;Sontheimer, Harald
谷胱甘肽（GSH）是一种重要的抗氧化剂，负责维持细胞内氧化还原稳态。随着肿瘤生长超过其血液供应并变得缺氧，其氧化还原稳态受到一氧化氮和活性氧（ROS）产生的挑战。在神经胶质瘤中，通过L-胱氨酸/L-谷氨酸交换器（系统xc（-））持续输入L-胱氨酸是GSH合成的速率限制。我们发现，缺氧导致NO和ROS的显着增加，但不影响胶质瘤细胞的生长。这可以通过GSH利用率的同时增加来解释，这伴随着xCT（系统xc（-）的催化亚基）和L-胱氨酸摄取的细胞表面表达的增加。生长受到抑制时，谷胱甘肽合成被阻断丁硫氨酸亚砜（BSO），谷胱甘肽合成所需的酶的抑制剂，或当细胞被剥夺的L-胱氨酸。这些发现表明，神经胶质瘤细胞表现出增加的GSH需求，以维持缺氧条件下的生长。因此，限制GSH合成的方法，如阻断系统xc（-），可以被认为是放疗或化疗的辅助手段。
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 xc(-), 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 xc(-), 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 xc(-) may be considered as an adjuvant to radiation or chemotherapy.