Expression of γ-glutamyltransferase in cancer cells and its significance in drug resistance

Abstract The expression of γ-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.

[1]  I. Melezínek,et al.  Tumour tissue is a source of gamma-glutamyl transpeptidase sialoform in the sera of melanoma-bearing mice. , 1998, Melanoma research.

[2]  M. Burt,et al.  gamma-Glutamyl transpeptidase mediation of tumor glutathione utilization in vivo. , 1996, Journal of the National Cancer Institute.

[3]  N. Taniguchi,et al.  Detection of a unique γ‐glutamyl transpeptidase messenger RNA species closely related to the development of hepatocellular carcinoma in humans: A new candidate for early diagnosis of hepatocellular carcinoma , 1996 .

[4]  P. Lipsky,et al.  Expression of γ-Glutamyl Transpeptidase Protects Ramos B Cells from Oxidation-induced Cell Death* , 2001, The Journal of Biological Chemistry.

[5]  D. Sarma,et al.  A common biochemical pattern in preneoplastic hepatocyte nodules generated in four different models in the rat. , 1985, Cancer research.

[6]  H. Frierson,et al.  Gamma-glutamyl transpeptidase immunoreactivity in benign and malignant breast tissue , 1997, Breast Cancer Research and Treatment.

[7]  D. Rouillard,et al.  gamma-Glutamyl transpeptidase expression in Ewing's sarcoma cells: up-regulation by interferons. , 2002, The Biochemical journal.

[8]  A. Paolicchi,et al.  Selective colocalization of lipid peroxidation and protein thiol loss in chemically induced hepatic preneoplastic lesions: the role of γ-glutamyltranspeptidase activity , 1996, Histochemistry and Cell Biology.

[9]  J. Carretero,et al.  Acceleration of Glutathione Efflux and Inhibition of γ-Glutamyltranspeptidase Sensitize Metastatic B16 Melanoma Cells to Endothelium-induced Cytotoxicity* , 2005, Journal of Biological Chemistry.

[10]  A. Paolicchi,et al.  Hydrogen peroxide produced during γ‐glutamyl transpeptidase activity is involved in prevention of apoptosis and maintainance of proliferation in U937 cells , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  D. Townsend,et al.  Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo. , 1999, Carcinogenesis.

[12]  A. Paolicchi,et al.  Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation. , 1999, Free radical biology & medicine.

[13]  N. Sawabu,et al.  Characterization of γ‐Glutamyltranspeptidase from Human Pancreatic Cancer , 1990 .

[14]  Yi Feng,et al.  Glutathione stimulates A549 cell proliferation in glutamine‐deficient culture: The effect of glutamate supplementation , 1994, Journal of cellular physiology.

[15]  F. Zunino,et al.  Protective effect of reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence on the therapeutic activity of the antitumor drug. , 1989, Chemico-biological interactions.

[16]  L. Lash.  Role of glutathione transport processes in kidney function. , 2005, Toxicology and applied pharmacology.

[17]  N. Thompson,et al.  Growth in culture and tumorigenicity after transfection with the ras oncogene of liver epithelial cells from carcinogen-treated rats. , 1987, Cancer research.

[18]  D. Munjal.  Concurrent measurements of carcinoembryonic antigen, glucosephosphate isomerase, gamma-glutamyltransferase, and lactate dehydrogenase in malignant, normal adult, and fetal colon tissues. , 1980, Clinical chemistry.

[19]  H. Gassen,et al.  γ-Glutamyl transpeptidase-cellular expression in populations of normal human mononuclear cells and patients suffering from leukemias , 1995, Annals of Hematology.

[20]  G. Siest,et al.  gamma-Glutamyltransferase dependent generation of reactive oxygen species from a glutathione/transferrin system. , 1998, Free radical biology & medicine.

[21]  D. Townsend,et al.  Inhibition of gamma-glutamyl transpeptidase or cysteine S-conjugate beta-lyase activity blocks the nephrotoxicity of cisplatin in mice. , 2002, The Journal of pharmacology and experimental therapeutics.

[22]  N. Rainov,et al.  Gamma-Glutamyl Transferase Expression in Higher-grade Astrocytic Glioma , 2001 .

[23]  H. Frierson,et al.  Altered expression of gamma-glutamyl transpeptidase in human tumors. , 1999, Human pathology.

[24]  R. Supino,et al.  Biological and enzymatic features of human melanoma clones with different invasive potential , 1992, Melanoma research.

[25]  H. Forman,et al.  Adaptation to oxidative stress: quinone-mediated protection of signaling in rat lung epithelial L2 cells. , 1997, Biochemical pharmacology.

[26]  D. Macdonald,et al.  Gamma glutamyl transpeptidase expression in foetal skin, inflammatory dermatoses and cutaneous neoplasia , 1991, The British journal of dermatology.

[27]  R. Boutwell,et al.  Localization and Significance of γ-Glutamyltranspeptidase in Normal and Neoplastic Mouse Skin , 1978 .

[28]  A. Meister,et al.  Translocation of intracellular glutathione to membrane-bound γ-glutamyl transpeptidase as a discrete step in the γ-glutamyl cycle: Glutathionuria after inhibition of transpeptidase , 1979 .

[29]  I. Schuppe-Koistinen,et al.  A role for gamma-glutamyl transpeptidase in the transport of cystine into human endothelial cells: relationship to intracellular glutathione. , 1994, Biochimica et biophysica acta.

[30]  F. Zunino,et al.  Endogenous Oxidative Stress Induces Distinct Redox Forms of Tumor Necrosis Factor Receptor‐1 in Melanoma Cells , 2004, Annals of the New York Academy of Sciences.

[31]  H. Yoshikawa,et al.  Role of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines , 2003, British Journal of Cancer.

[32]  N. Heisterkamp,et al.  Transfection with gamma-glutamyl transpeptidase enhances recovery from glutathione depletion using extracellular glutathione. , 1992, Toxicology and applied pharmacology.

[33]  M. Burt,et al.  Glutathione metabolism in patients with non-small cell lung cancers. , 1997, Cancer research.

[34]  R. Nordquist,et al.  Elevated γ‐glutamyl transpeptidase levels in malignant melanoma , 1982 .

[35]  Yi Wang,et al.  Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Visvikis,et al.  The changing faces of glutathione, a cellular protagonist. , 2003, Biochemical pharmacology.

[37]  E. Zeiger,et al.  Glutathione metabolism by gamma-glutamyltranspeptidase leads to lipid peroxidation: characterization of the system and relevance to hepatocarcinogenesis. , 1993, Carcinogenesis.

[38]  M. Uysal,et al.  Increased lipoperoxide levels and antioxidant system in colorectal cancer , 1998, Journal of Cancer Research and Clinical Oncology.

[39]  C. Wolf,et al.  Glutathione and glutathione-dependent enzymes in ovarian adenocarcinoma cell lines derived from a patient before and after the onset of drug resistance: intrinsic differences and cell cycle effects. , 1988, Carcinogenesis.

[40]  W. Fishman,et al.  Demonstration of gamma-glutamyl transferase, alkaline phosphatase, CEA and HCG in human lung cancer. , 1981, Oncodevelopmental biology and medicine : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[41]  F. Chauvin,et al.  gamma-Glutamyltranspeptidase activity in human breast lesions: an unfavourable prognostic sign. , 1986, British Journal of Cancer.

[42]  P. Taylor,et al.  Cisplatin nephrotoxicity: inhibition of gamma-glutamyl transpeptidase blocks the nephrotoxicity of cisplatin without reducing platinum concentrations in the kidney. , 1996, American journal of obstetrics and gynecology.

[43]  M. Galteau,et al.  Enhanced resistance of HeLa cells to cisplatin by overexpression of γ-glutamyltransferase , 2002 .

[44]  F. Oesch,et al.  Gamma-glutamyl transpeptidase and glutathione biosynthesis in non-tumorigenic and tumorigenic rat liver oval cell lines. , 2001, Carcinogenesis.

[45]  P. Apostoli,et al.  gamma-Glutamyl transpeptidase catalyses the extracellular detoxification of cisplatin in a human cell line derived from the proximal convoluted tubule of the kidney. , 2003, European journal of cancer.

[46]  D. Vistica,et al.  γ‐glutamyl transpeptidase (γ‐GT) and maintenance of thiol pools in tumor cells resistant to alkylating agents , 1987 .

[47]  H. Frierson,et al.  gamma-Glutamyl transpeptidase in normal and neoplastic prostate glands. , 1997, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[48]  M. Hanigan.  Expression of gamma-glutamyl transpeptidase provides tumor cells with a selective growth advantage at physiologic concentrations of cyst(e)ine. , 1995, Carcinogenesis.

[49]  H. Frierson,et al.  Human germ cell tumours: expression of γ-glutamyl transpeptidase and sensitivity to cisplatin , 1999, British Journal of Cancer.

[50]  G. Schaaf,et al.  Beta-lyase-dependent attenuation of cisplatin-mediated toxicity by selenocysteine Se-conjugates in renal tubular cell lines. , 2002, The Journal of pharmacology and experimental therapeutics.

[51]  Zhijian Yu,et al.  Abnormal expression of hepatoma specific γ‐glutamyl transferase and alteration of γ‐glutamyl transferase gene methylation status in patients with hepatocellular carcinoma , 2000 .

[52]  A. Godwin,et al.  High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[53]  A. Corti,et al.  The S-thiolating activity of membrane gamma-glutamyltransferase: formation of cysteinyl-glycine mixed disulfides with cellular proteins and in the cell microenvironment. , 2005, Antioxidants & redox signaling.

[54]  J. Sastre,et al.  A role for gamma‐glutamyl transpeptidase and the amino acid transport system xc‐ in cystine transport by a human pancreatic duct cell line. , 1995, The Journal of physiology.

[55]  M. Anderson,et al.  Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[56]  H. Kozakova,et al.  Cisplatin induced gamma-glutamyltransferase up-regulation, hypertrophy and differentiation in astrocytic glioma cells in culture. , 2003, Histology and Histopathology.

[57]  L. Kauvar,et al.  Glutathione based approaches to improving cancer treatment. , 1998, Chemico-biological interactions.

[58]  H. Ding,et al.  Diagnostic value of protein induced by vitamin K absence (PIVKAII) and hepatoma-specific band of serum gamma-glutamyl transferase (GGTII) as hepatocellular carcinoma markers complementary to α-fetoprotein , 2003, British Journal of Cancer.

[59]  H. Frierson,et al.  Immunohistochemical detection of gamma-glutamyl transpeptidase in normal human tissue. , 1996, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[60]  D. Townsend,et al.  (cid:2) -Glutamyl Transpeptidase-Deficient Mice Are Resistant to the Nephrotoxic Effects of Cisplatin , 2001 .

[61]  A. Corti,et al.  Prooxidant reactions promoted by soluble and cell-bound gamma-glutamyltransferase activity. , 2005, Methods in enzymology.

[62]  E. Zeiger,et al.  Localization of oxidative damage by a glutathione-gamma-glutamyl transpeptidase system in preneoplastic lesions in sections of livers from carcinogen-treated rats. , 1994, Carcinogenesis.

[63]  F. Zunino,et al.  The role of the glutathione-dependent system in tumor sensitivity to cisplatin: a study of human tumor xenografts. , 1995, Annals of oncology : official journal of the European Society for Medical Oncology.

[64]  F. Zunino,et al.  The cell‐specific anti‐proliferative effect of reduced glutathione is mediated by γ‐glutamyl transpeptidase‐dependent extracellular pro‐oxidant reactions , 1997, International journal of cancer.

[65]  H. Pitot,et al.  Gamma-glutamyl transpeptidase--its role in hepatocarcinogenesis. , 1985, Carcinogenesis.

[66]  J. Carretero,et al.  γ‐Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver , 2002, Hepatology.

[67]  H. Frierson,et al.  Expression of γ-glutamyl transpeptidase in stage III and IV ovarian surface epithelial carcinomas does not alter response to primary cisplatin-based chemotherapy , 1998 .

[68]  H. Forman,et al.  Extracellular glutathione and gamma-glutamyl transpeptidase prevent H2O2-induced injury by 2,3-dimethoxy-1,4-naphthoquinone. , 1993, Free radical biology & medicine.

[69]  A. Visvikis,et al.  Different mechanisms for γ-glutamyltransferase-dependent resistance to carboplatin and cisplatin , 2003 .

[70]  F. Zunino,et al.  Ovarian cancer cisplatin-resistant cell lines: multiple changes including collateral sensitivity to Taxol. , 1998, Annals of oncology : official journal of the European Society for Medical Oncology.

[71]  A. Gadducci,et al.  Gamma-glutamyltranspeptidase activity in human ovarian carcinoma. , 1996, Anticancer research.

[72]  A. Lichtenstein,et al.  Sulfur-containing amino acids decrease cisplatin cytotoxicity and uptake in renal tubule epithelial cell lines , 2000, Cancer Chemotherapy and Pharmacology.

[73]  W. Ricketts,et al.  Extracellular glutathione is a source of cysteine for cells that express gamma-glutamyl transpeptidase. , 1993, Biochemistry.

[74]  A. Paolicchi,et al.  Glutathione catabolism as a signaling mechanism. , 2002, Biochemical pharmacology.

[75]  T. Slaga,et al.  Induction and Inhibition of Tumor Progression , 1993, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.