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

Background. The purpose of this study was to investigate expression of gamm a glutamyl cysteine synthetase (gamma GCS), the rate-limiting enzyme in glu tathione synthesis in nonsmall cell lung carcinoma (NSCLC). Methods. Eighty-five samples of NSCLC were studied using immunohistochemist ry with polyclonal antibodies to the heavy and light subunits of gamma GCS (gamma GCS-h, gamma GCS-1), and the expressions were-correlated with apotos is and patients survival. Further studies were conducted in cultured cells also to investigate the effects of gamma GSC inhibition with buthionine sul foximine on the cell survival. Results. In the biopsies, gamma GCS-h positivity was found in 71% and gamma GCS-1 positivity in 67% of NSCLCs, and they were expressed in all cell lin es studied. There was a strong association between the expression of the he avy 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 signi ficantly higher extent of apoptosis in tumors with a low gamma GCS-h expres sion (P=0.016). A similar tendency was observed with gamma GCS-1 (P=0.073). No association was found between patient survival and high or low expressi on of gamma GCS-1 or gamma GCS-h in NSCLCs (P=0.34 and P=0.47, respectively ). Conclusions. The results show that gamma GCS is strongly expressed in NSCLC s and probably takes part in the defense of the tumor cells against oxidati ve damage. This is reflected by the lower extent of apoptosis in tumors wit h a high gamma GCS expression. Because expression of gamma GCS has been con nected with chemoresistance, downregulation of its activity by inhibitors i n NSCLC might have putative therapeutic potential in the treatment of lung carcinoma. Cancer 2001;92:2911-9. (C) 2001 American Cancer Society.