Franzini Maria, Corti Alessandro, Lorenzini Evelina, Paolicchi Aldo, Pompella Alfonso, De Cesare Michelandrea, Perego Paola, Gatti Laura, Leone Roberto, Apostoli Pietro, Zunino Franco
Dipartimento di Patologia Sperimentale BMIE, University of Pisa Medical School, Italy.
Eur J Cancer. 2006 Oct;42(15):2623-30. doi: 10.1016/j.ejca.2006.04.016. Epub 2006 Aug 22.
The plasma membrane enzyme gamma-glutamyltransferase (GGT) is regarded as critical for the maintenance of intracellular levels of glutathione (GSH). GGT expression has been implicated in drug resistance through elevation of intracellular GSH. The dependence of intracellular GSH on GGT expression was not conclusively ascertained. The present study was designed to investigate the role of GGT and of intracellular GSH levels in modulating proliferation and sensitivity to cisplatin of melanoma cells. GGT transfection resulted in increased growth, both in vitro and in tumour xenografts. In addition, GGT-transfected cells exhibited reduced sensitivity to cisplatin associated with lower DNA platination. A decrease in intracellular GSH levels, rather than an increase, was observed in GGT-transfected cells; moreover, in cysteine-deficient conditions, the expression of GGT did not provide transfected cells with the ability of utilising extracellular GSH. In conclusion, these results indicate that GGT activity confers a growth advantage unrelated with intracellular glutathione supply, and are consistent with the interpretation that cisplatin resistance is the consequence of modifications of cellular pharmacokinetics as a result of extracellular drug inactivation by thiol metabolites originated by GGT-mediated GSH cleavage.
质膜酶γ-谷氨酰转移酶（GGT）被认为对维持细胞内谷胱甘肽（GSH）水平至关重要。GGT的表达通过提高细胞内GSH水平与耐药性有关。细胞内GSH对GGT表达的依赖性尚未得到最终确定。本研究旨在探讨GGT和细胞内GSH水平在调节黑色素瘤细胞增殖和顺铂敏感性方面的作用。GGT转染导致体外和肿瘤异种移植中生长增加。此外，GGT转染的细胞对顺铂的敏感性降低，与较低的DNA铂化有关。在GGT转染的细胞中观察到细胞内GSH水平降低而非升高；此外，在半胱氨酸缺乏的条件下，GGT的表达并未使转染细胞具备利用细胞外GSH的能力。总之，这些结果表明GGT活性赋予了一种与细胞内谷胱甘肽供应无关的生长优势，并且与以下解释一致，即顺铂耐药是由于GGT介导的GSH裂解产生的硫醇代谢产物使细胞外药物失活从而导致细胞药代动力学改变的结果。
