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Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma.

ABSTRACT: 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 ?M), all the stable cell lines were more resistant to cisplatin (12.9 ?M, P = 0.025; 13.9 ?M, P = 0.028; 26.7 ?M, P = 0.001; 17.7 ?M, 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.

SUBMITTER: Hiyama N

PROVIDER: S-EPMC5892860 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma.

Hiyama Noriko N Ando Takahiro T Maemura Keita K Sakatani Toshio T Amano Yosuke Y Watanabe Kousuke K Kage Hidenori H Yatomi Yutaka Y Nagase Takahide T Nakajima Jun J Takai Daiya D

Japanese journal of clinical oncology 20180401 4

<h4>Background</h4>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.<h4>Methods</h4>We established cell lines stably expressing GCLC, xCT, standard isoform of CD44, and C ...[more]

PMID: 29474642

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Project description:BackgroundLung cancer is the most common malignant tumor in the world. The Whole-proteome microarray showed that ubiquitin ligase chromatin assembly factor 1 subunit B (CHAF1B) expression in A549/DDP cells is higher than in A549 cells. Our study explored the molecular mechanism of CHAF1B affecting cisplatin resistance in lung adenocarcinoma (LUAD).MethodsProteome microarray quantify the differentially expressed proteins between LUAD cell line A549 and its cisplatin-resistant strain A549/DDP. Quantitative real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot (WB) confirmed the CHAF1B expression. Public databases analyzed the prognosis of LUAD patients with varied LUAD expression followed by the substrates prediction of CHAF1B. Public databases showed that nuclear receptor corepressor 2 (NCOR2) may be substrates of CHAF1B. WB detected that CHAF1B expression affected the expression of NCOR2. Cell and animal experiments and clinical data detected function and integrating mechanism of CHAF1B compounds.ResultsProteome chips results indicated that CHAF1B, PPP1R13L, and CDC20 was higher than A549 in A549/DDP. Public databases showed that high expression of CHAF1B, PPP1R13L, and CDC20 was negatively correlated with prognosis in LUAD patients. PCR and WB results indicated higher CHAF1B expression in A549/DDP cells than that in A549 cells. NCOR2 and PPP5C were confirmed to be substrates of CHAF1B. CHAF1B knockdown significantly increased the sensitivity of cisplatin in A549/DDP cells and the upregulated NCOR2 expression. CHAF1B and NCOR2 are interacting proteins and the position of interaction between CHAF1B and NCOR2 was mainly in the nucleus. CHAF1B promotes ubiquitination degradation of NCOR2. Cells and animal experiments showed that under the action of cisplatin, after knockdown of CHAF1B and NCOR2 in A549/DDP group compared with CHAF1B knockdown alone, the cell proliferation and migratory ability increased and apoptotic rate decreased, and the growth rate and size of transplanted tumor increased significantly. Immunohistochemistry suggested that Ki-67 increased, while apoptosis-related indicators caspase-3 decreased significantly. Clinical data showed that patients with high expression of CHAF1B are more susceptible to cisplatin resistance.ConclusionUbiquitin ligase CAHF1B can induce cisplatin resistance in LUAD by promoting the ubiquitination degradation of NCOR2.

Dataset Information

Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma.

Publications

Glutamate-cysteine ligase catalytic subunit is associated with cisplatin resistance in lung adenocarcinoma.

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