γ-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver

Publisher Website
Google Scholar
Abstract
B16 melanoma (B16M) cells with high glutathione (GSH) content show rapid proliferation in vitro and high metastatic activity in the liver in vivo. γ-Glutamyl transpeptidase (GGT)-mediated extracellular GSH cleavage and intracellular GSH synthesis were studied in vitro in B16M cells with high (F10) and low (F1) metastatic potential. GGT activity was modified by transfection with the human GGT gene (B16MF1/Tet-GGT cells) or by acivicin-induced inhibition. B16MF1/Tet-GGT and B16MF10 cells exhibited higher GSH content (35 ± 6 and 40 ± 5 nmol/106 cells, respectively) and GGT activity (89 ± 9 and 37 ± 7 mU/106 cells, respectively) as compared (P < .05) with B16MF1 cells (10 ± 3 nmol GSH and 4 mU GGT/106 cells). Metastasis (number of foci/100 mm3 of liver) increased in B16MF1 cells pretreated with GSH ester (˜3-fold, P < .01), and decreased in B16MF1/Tet-GGT and B16MF10 cells pretreated with the GSH synthesis inhibitor L-buthionine (S,R)-sulphoximine (˜5-fold and 2-fold, respectively, P < .01). Liver, kidney, brain, lung, and erythrocyte GSH content in B16MF1/Tet-GGT- or B16MF10-bearing mice decreased as compared with B16MF1- and non-tumor-bearing mice. Organic anion transporting polypeptide 1-independent sinusoidal GSH efflux from hepatocytes increased in B16MF1/Tet-GGT- or B16MF10-bearing mice (˜2-fold, P < .01) as compared with non-tumor-bearing mice. Our results indicate that tumor GGT activity and an intertissue flow of GSH can regulate GSH content of melanoma cells and their metastatic growth in the liver.
Keywords
Funding Information
  • CICYT (Saf99-112, 1FD97-548)
  • J.C. and A.O.
  • Fundación Científica de la AECC and the MCYT

This publication has 47 references indexed in Scilit: