{gamma}-Glutamyltransferase (GGT), involved in metabolism of glutathione (GSH), can promote prooxidant reactions (Dominici et al, Meth Enzymol 2005) both extra- and intracellularly, resulting e.g. in activation of NF-kB (Maellaro et al, J Cell Sci 2000). Cancer cells often overexpress GGT, along with increased resistance to cisplatin. A role of GGT in cellular supply of GSH remains questionable (Pompella et al, Biochem Pharm 2006). We have observed that: proliferation of GGT-transfected melanoma cells is increased, both in culture and in vivo in athymic mice, resistance to cisplatin is also increased, but intracellular GSH levels are decreased. Thus, drug resistance offered by GGT is likely the result of a process of "extracellular detoxication", as previously envisaged (Paolicchi et al, Eur J Cancer 2003). On the other hand, previous studies showed that GGT can effect a redox regulation of PARP activity (Del Bello et al, FASEB J 1999), likely due to some degree of (oxidative) DNA damage. In melanoma as well as in prostatic cancer cells, we observed that: GGT-transfected cells present with higher DNA damage levels (Comet assay), the specific inhibition of GGT restores control levels of damage, while DNA repair systems appear unmodified. Expression of GGT may thus represent a critical factor in acceleration of cancer progression.

The expression of gamma-glutamyltransferase in cancer cells is a factor in genomic instability, progression and drug resistance.

POMPELLA, ALFONSO;CORTI, ALESSANDRO;FRANZINI, MARIA;DOMINICI, SILVIA;PAOLICCHI, ALDO
2007-01-01

Abstract

{gamma}-Glutamyltransferase (GGT), involved in metabolism of glutathione (GSH), can promote prooxidant reactions (Dominici et al, Meth Enzymol 2005) both extra- and intracellularly, resulting e.g. in activation of NF-kB (Maellaro et al, J Cell Sci 2000). Cancer cells often overexpress GGT, along with increased resistance to cisplatin. A role of GGT in cellular supply of GSH remains questionable (Pompella et al, Biochem Pharm 2006). We have observed that: proliferation of GGT-transfected melanoma cells is increased, both in culture and in vivo in athymic mice, resistance to cisplatin is also increased, but intracellular GSH levels are decreased. Thus, drug resistance offered by GGT is likely the result of a process of "extracellular detoxication", as previously envisaged (Paolicchi et al, Eur J Cancer 2003). On the other hand, previous studies showed that GGT can effect a redox regulation of PARP activity (Del Bello et al, FASEB J 1999), likely due to some degree of (oxidative) DNA damage. In melanoma as well as in prostatic cancer cells, we observed that: GGT-transfected cells present with higher DNA damage levels (Comet assay), the specific inhibition of GGT restores control levels of damage, while DNA repair systems appear unmodified. Expression of GGT may thus represent a critical factor in acceleration of cancer progression.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/758166
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