Expression of γ-glutamyl cysteine synthetase in nonsmall cell lung carcinoma

Abstract

BACKGROUND. The purpose of this study was to investigate expression of gamma glutamyl cysteine synthetase (γGCS), the rate-limiting enzyme in glutathione synthesis in nonsmall cell lung carcinoma (NSCLC). METHODS. Eighty-five samples of NSCLC were studied using immunohistochemistry with polyclonal antibodies to the heavy and light subunits of γGCS (γGCS-h, γGCS-1), and the expressions were correlated with apotosis and patients survival. Further studies were conducted in cultured cells also to investigate the effects of γGSC inhibition with buthionine sulfoximine on the cell survival. RESULTS. In the biopsies, γGCS-h positivity was found in 71% and γGCS-1 positivity in 67% of NSCLCs, and they were expressed in all cell lines studied. There was a strong association between the expression of the heavy and light subunits of γGCS in NSCLC (P = 0.003). Strong or moderate γGCS-h expression was found significantly more often in squamous cell carcinomas (P = 0.00013) and in Grade 1-2 tumors (P = 0.008). There was a significantly higher extent of apoptosis in tumors with a low γGCS-h expression (P = 0.016). A similar tendency was observed with γGCS-1 (P = 0.073). No association was found between patient survival and high or low expression of γGCS-1 or γGCS-h in NSCLCs (P = 0.34 and P = 0.47, respectively). C0NCLUSlONS. The results show that γGCS is strongly expressed in NSCLCs and probably takes part in the defense of the tumor cells against oxidative damage. This is reflected by the lower extent of apoptosis in tumors with a high γGCS expression. Because expression of γGCS has been connected with chemoresistance, down-regulation of its activity by inhibitors in NSCLC might have putative therapeutic potential in the treatment of lung carcinoma. © 2001 American Cancer Society.