Expression of γ-glutamyltransferase in cancer cells and its significance in drug resistance
Expression of γ-glutamyltransferase in cancer cells and its significance in drug resistance
复制标题
DOI：
10.1016/j.bcp.2005.10.005
复制
发表时间：
2006-01-12
影响因子：
5.8
通讯作者：
Zunino, F
中科院分区：
文献类型：
--
作者：
Pompella, A;De Tata, V;Zunino, F
γ-谷氨酰转移酶（GGT）是一种参与细胞谷胱甘肽稳态的细胞表面酶，其表达在人类肿瘤中通常显著增加，并且其在肿瘤进展、侵袭和耐药性中的作用已被反复提出。由于GGT参与细胞谷胱甘肽的代谢，其活性主要被认为是细胞抗氧化/抗毒防御重建的一个因素。在此基础上，已经设想了GGT表达参与癌细胞对细胞毒性药物（特别是顺铂和其他亲电子试剂）的抗性。然而，GGT参与抗肿瘤药理学的机制方面值得进一步研究。最近的证据表明，GGT在调节氧化还原平衡中具有更复杂的作用，其作用在细胞内和细胞外微环境中。存在的迹象表明，GGT的保护作用可能是独立的细胞内谷胱甘肽，而来自过程发生在细胞外水平，涉及亲电子药物与巯基代谢物的反应，从GGT介导的细胞外谷胱甘肽的裂解。虽然GGT的表达不能被视为耐药的一般机制，但预期该酶参与氧化还原代谢的调节对细胞对几种细胞毒性剂的反应有影响。本文综述了GGT在肿瘤细胞生物学中的作用及其在肿瘤耐药中的作用机制。(c)2005年爱思唯尔公司All rights reserved.
The expression of gamma-glutamyltransferase (GGT), a cell surface enzyme involved in cellular glutathione homeostasis, is often significantly increased in human tumors, and its role in tumor progression, invasion and drug resistance has been repeatedly suggested. As GGT participates in the metabolism of cellular glutathione, its activity has been mostly regarded as a factor in reconsitution of cellular antioxidant/antitoxic defences. On this basis, an involvement of GGT expression in resistance of cancer cells to cytotoxic drugs (in particular, cisplatin and other electrophilic agents) has been envisaged. Mechanistic aspects of GGT involvement in antitumor pharmacology deserve however further investigations. Recent evidence points to a more complex role of GGT in modulation of redox equilibria, with effects acting both intracellularly and in the extracellular microenvironment. Indications exist that the protective effects of GGT may be independent of intracellular glutathione, and derive rather from processes taking place at extracellular level and involving reactions of electrophilic drugs with thiol metabolites originating from GGT-mediated cleavage of extracellular glutathione. Although expression of GGT cannot be regarded as a general mechanism of resistance, the involvement of this enzyme in modulation of redox metabolism is expected to have impact in cellular response to several cytotoxic agents. The present commentary is a survey of data concerning the role of GGT in tumor cell biology and the mechanisms of its potential involvement in tumor drug resistance. (c) 2005 Elsevier Inc. All rights reserved.