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

The purpose of this study was to investigate expression of gamma glutamyl cysteine synthetase (gamma GCS), the rate-limiting enzyme in glutathione synthesis in nonsmall cell lung carcinoma (NSCLC).

Eighty-five samples of NSCLC were studied using immunohistochemistry with polyclonal antibodies to the heavy and light subunits of gamma GCS (gamma GCS-h, gamma GCS-l), and the expressions were correlated with apoptosis and patients survival. Further studies were conducted in cultured cells also to investigate the effects of gamma GSC inhibition with buthionine sulfoximine on the cell survival.

In the biopsies, gamma GCS-h positivity was found in 71% and gamma GCS-l 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 gamma GCS in NSCLC (P = 0.003). Strong or moderate gamma GCS-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 gamma GCS-h expression (P = 0.016). A similar tendency was observed with gamma GCS-l (P = 0.073). No association was found between patient survival and high or low expression of gamma GCS-l or gamma GCS-h in NSCLCs (P = 0.34 and P = 0.47, respectively).

The results show that gamma GCS 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 gamma GCS expression. Because expression of gamma GCS has been connected with chemoresistance, downregulation of its activity by inhibitors in NSCLC might have putative therapeutic potential in the treatment of lung carcinoma.