Reference - Detail
|Author||Hiyama N, Ando T, Maemura K, Sakatani T, Amano Y, Watanabe K, Kage H, Yatomi Y, Nagase T, Nakajima J, Takai D.|
|Title||Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma.|
|Journal||Jpn. J. Clin. Oncol.|
Background:Cisplatin is a key drug for treating lung adenocarcinoma, and its sensitivity to cisplatin is directly related to prognosis. We aimed to reveal the roles of genes related to glutathione synthesis (glutamate-cysteine ligase catalytic subunit, GCLC) and cystine uptake (cystine/glutamate transporter, xCT and CD44v8-10) in cisplatin resistance and prognosis in lung adenocarcinoma.
Methods:We established cell lines stably expressing GCLC, xCT, standard isoform of CD44, and CD44v8-10, and investigated their sensitivities to cisplatin. We also measured mRNA expression levels of these genes in the tumor tissues from 92 lung adenocarcinoma patients. Patients were divided into high-expression (upper quartile, N = 23) and low-expression groups (remaining patients, N = 69). Recurrence-free survival, overall survival (N = 92), and post-recurrence survival (N = 22) were selected as endpoints.
Results:Compared with the control green fluorescent protein-expressing cell line (inhibitory concentration 50:6.9 μM), all the stable cell lines were more resistant to cisplatin (12.9 μM, P = 0.025; 13.9 μM, P = 0.028; 26.7 μM, P = 0.001; 17.7 μM, P = 0.008, respectively). In contrast, there was no significant difference in recurrence-free or overall survival between the high- and low-expression groups for any of the genes. However, high expression of GCLC was a risk factor for poorer post-recurrence survival (hazard ratio, 6.26; 95% confidence interval, 1.37-28.7; P = 0.018).
Conclusion:High expression levels of genes related to glutathione synthesis and cystine uptake promote cisplatin resistance in lung adenocarcinoma cell lines. High expression of GCLC in tumor tissue may be a potential predictor of treatment failure.
|MeSH||Adenocarcinoma / drug therapy* Adenocarcinoma / enzymology* Adenocarcinoma / genetics Adenocarcinoma / pathology Aged Catalytic Domain* Cell Line, Tumor Cisplatin / pharmacology Cisplatin / therapeutic use* Drug Resistance, Neoplasm* / drug effects Female Gene Expression Regulation, Neoplastic / drug effects Glutamate-Cysteine Ligase / genetics Glutamate-Cysteine Ligase / metabolism* Humans Inhibitory Concentration 50 Lung Neoplasms / drug therapy* Lung Neoplasms / enzymology* Lung Neoplasms / genetics Lung Neoplasms / pathology RNA, Messenger / genetics RNA, Messenger / metabolism Survival Analysis|
|DNA material||CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394).|