Gamma-glutamyl transpeptidase: redox regulation and drug resistance.
Gamma-glutamyl transpeptidase: redox regulation and drug resistance.
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DOI：
10.1016/b978-0-12-420117-0.00003-7
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发表时间：
2014
影响因子：
--
通讯作者：
Hanigan, Marie H.
中科院分区：
文献类型：
--
作者：
Hanigan, Marie H.
γ-谷氨酰转肽酶(GGT)的表达是维持体内半胱氨酸水平所必需的。GGT是一种细胞表面酶，它能将细胞外还原和氧化的谷胱甘肽的γ-谷氨酰键水解酶，使其裂解成谷氨酸、半胱氨酸和甘氨酸。GGT通常表达在导管和腺体的顶端表面，从导管液体中的谷胱甘肽中回收氨基酸。肿瘤中的GGT表达在整个细胞膜上，并为肿瘤提供了从血液和间质液中还原和氧化的谷胱甘肽获得额外半胱氨酸和半胱氨酸的途径。半胱氨酸是氧化应激下细胞谷胱甘肽合成的限速物质。在细胞内谷胱甘肽水平升高的肿瘤中可以观察到GGT的诱导。在肝癌发生模型中的研究表明，癌前肝细胞灶中GGT的表达为细胞在耗尽细胞内谷胱甘肽的促癌过程中提供了选择性优势。同样，GGT在肿瘤中的表达使细胞能够维持细胞内高水平的谷胱甘肽，并在抗氧化剂抗癌治疗期间迅速补充谷胱甘肽。在临床上，GGT在肿瘤中的表达与耐药有关。GGT的抑制剂阻止GGT阳性肿瘤进入细胞外谷胱甘肽的半胱氨酸。它们还抑制肾脏中的GGT活性，导致尿中GSH排泄，并迅速降低血液半胱氨酸水平，导致GGT阳性和GGT阴性肿瘤的细胞内GSH耗尽。GGT抑制剂正在开发用于临床，以增加肿瘤对化疗的敏感性。
Expression of gamma-glutamyl transpeptidase (GGT) is essential to maintaining cysteine levels in the body. GGT is a cell surface enzyme that hydrolyzes the gamma-glutamyl bond of extracellular reduced and oxidized glutathione, initiating their cleavage into glutamate, cysteine (cystine) and glycine. GGT is normally expressed on the apical surface of ducts and glands, salvaging the amino acids from glutathione in the ductal fluids. GGT in tumors is expressed over the entire cell membrane and provides tumors with access to additional cysteine and cystine from reduced and oxidized glutathione in the blood and interstitial fluid. Cysteine is rate-limiting for glutathione synthesis in cells under oxidative stress. Induction of GGT is observed in tumors with elevated levels of intracellular glutathione. Studies in models of hepatocarcinogenesis show that GGT expression in foci of preneoplastic hepatocytes provides a selective advantage to the cells during tumor promotion with agents that deplete intracellular glutathione. Similarly, expression of GGT in tumors enables cells to maintain elevated levels of intracellular glutathione and to rapidly replenish glutathione during treatment with pro-oxidant anti-cancer therapy. In the clinic, expression of GGT in tumors is correlated with drug resistance. Inhibitors of GGT block GGT-positive tumors from accessing the cysteine in extracellular glutathione. They also inhibit GGT activity in the kidney, which results in excretion of GSH in the urine, and a rapid decrease in blood cysteine levels, leading to depletion of intracellular GSH in both GGT-positive and GGT-negative tumors. GGT inhibitors are being developed for clinical use to sensitize tumors to chemotherapy.