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

Hiyama, Noriko; Ando, Tomohiro; Maemura, Kouji; Sakatani, Toshio; Amano, Yosuke; Watanabe, Kousuke; Kage, Hidenori; Yatomi, Yutaka; Nagase, Takahide; Nakajima, Jun; Takai, Daiya

doi:10.1093/jjco/hyy013

Cited by 24 publications

(15 citation statements)

References 26 publications

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“…The intracellular glutathione pool is regulated by a series of enzymes involved in its synthesis, utilization and recycling, and high expression levels of these genes have been seen to promote cisplatin resistance in lung adenocarcinoma cell lines, with the glutamate cysteine ligase catalytic subunit (GCLC) expression being proposed as a potential predictor of treatment failure 30 . Importantly, the expression of these genes is controlled by the transcription factor NRF2, and several studies have shown that high amounts of NRF2 can induce cisplatin resistance in ovarian, bladder, and head and neck cancers 31–33 .…”

Section: Discussionmentioning

confidence: 99%

The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

Silva

Rocha

Kinker

et al. 2019

Sci Rep

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Lung cancer patients face a dismal prognosis mainly due to the low efficacy of current available treatments. Cisplatin is the first-line chemotherapy treatment for those patients, however, resistance to this drug is a common and yet not fully understood phenomenon. Aiming to shed new light into this puzzle, we used established normal and malignant lung cell lines displaying different sensitivity towards cisplatin treatment. We observed a negative correlation between cell viability and DNA damage induction upon cisplatin treatment. Interestingly, drug sensitivity in those cell lines was not due to either difference on DNA repair capacity, or in the amount of membrane ion channel commonly used for cisplatin uptake. Also, we noted that glutathione intracellular levels, and expression and activity of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene expression in non-small cell lung cancer patients of the TCGA data bank revealed that there is a significant lower overall survival rate in the subset of patients bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, increased expression of NRF2 target genes. Thus, the results indicate that NRF2 and glutathione levels figure as important cisplatin resistance biomarkers in lung cancer.

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Section: Discussionmentioning

confidence: 99%

The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

Silva

Rocha

Kinker

et al. 2019

Sci Rep

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“…Nevertheless, majority of patients still suffer from the reoccurring LAC [5]. Moreover, cisplatin has been shown to be essential when treating LAC, with its sensitivity to cisplatin being directly associated to the prognosis [6]. In previous studies, by inhibiting contactin-1, the sensitivity levels of LAC increase, thereby affecting the chemotherapeutic efficacy related to cisplatin based regimens among patients suffering from LAC [7].…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA LINC00485 acts as a microRNA-195 sponge to regulate the chemotherapy sensitivity of lung adenocarcinoma cells to cisplatin by regulating CHEK1

Zuo

Zhang

et al. 2019

Cancer Cell Int

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Background Long non-coding RNAs (lncRNAs) are a family of non-protein-coding RNAs, which have the ability to influence the chemo-resistance of lung adenocarcinoma (LAC). In this study, we explored the mechanism by which LINC00485 competitively binds to microRNA-195 (miR-195) in the regulation of the chemotherapy sensitivity in LAC by regulating checkpoint kinase 1 (CHEK1). Methods Microarray analysis was used to screen out LAC related genes, and interaction between CHEK1 and miR-195, as well as that between miR-195 and LINC00485, was further confirmed by RNA-pull down and RIP. LINC00485 expression in LAC cells (A549 and H1299) was determined. The cells were then introduced with miR-195, anta-miR-195, LINC00485 or si-LINC00485 to identify the role of miR-195 and LINC00485 in LAC through evaluating the expression of CHEK1, CHEK1, Bax, Bcl-2, VEGF and HIF-1α in LAC cells by either RT-qPCR or Western blot analysis. After being treated with different concentration of cisplatin, cell proliferation, colony formation and apoptosis were assessed. Results LINC00485 acted as a competitive endogenous RNA against miR-195, and miR-195 directly targeted CHEK1. The expression of LINC00485 was higher in LAC cells. The down-regulation of LINC00485 or the up-regulation of miR-195 decreased the expression of CHEK1, Bcl-2, VEGF and HIF-1α, while also increasing the expression of Bax. Moreover, the over-expression of miR-195, or the silencing of LINC00485 enhanced the sensitivity of LAC cells to cisplatin, thereby promoting the apoptosis of LAC cells while suppressing the proliferation. Conclusion LINC00485 competitively binds to miR-195 to elevate CHEK1 expression in LAC cells, suggesting that LINC00485 is a novel direction for therapeutic strategies of LAC.

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“…As well, GCLC has been found to overexpress in liver metastases of colorectal cancer and promotes cancer cell survival ( 47 ). Also, GCLC activation is associated with anti-tumor drug resistance in breast, lung, liver, head, and neck cancer ( 37 , 48 – 50 ). Based on our in silico results and previous studies, we propose that both ANPEP and GCL have key roles in EMT development, however prognostic significance, as well as its potential as a pharmacological target, requires further in-depth investigations.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Epithelial-Mesenchymal Transition Metabolism Identifies Possible Cancer Biomarkers Useful in Diverse Genetic Backgrounds

Matadamas-Guzman

Zazueta

Rojas³

et al. 2020

Front. Oncol.

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Epithelial-to-mesenchymal transition (EMT) relates to many molecular and cellular alterations that occur when epithelial cells undergo a switch in differentiation generating mesenchymal-like cells with newly acquired migratory and invasive properties. In cancer cells, EMT leads to drug resistance and metastasis. Moreover, differences in genetic backgrounds, even between patients with the same type of cancer, also determine resistance to some treatments. Metabolic rewiring is essential to induce EMT, hence it is important to identify key metabolic elements for this process, which can be later used to treat cancer cells with different genetic backgrounds. Here we used a mathematical modeling approach to determine which are the metabolic reactions altered after induction of EMT, based on metabolomic and transcriptional data of three non-small cell lung cancer (NSCLC) cell lines. The model suggested that the most affected pathways were the Krebs cycle, amino acid metabolism, and glutathione metabolism. However, glutathione metabolism had many alterations either on the metabolic reactions or at the transcriptional level in the three cell lines. We identified Glutamate-cysteine ligase (GCL), a key enzyme of glutathione synthesis, as an important common feature that is dysregulated after EMT. Analyzing survival data of men with lung cancer, we observed that patients with mutations in GCL catalytic subunit (GCLC) or Glutathione peroxidase 1 (GPX1) genes survived less time than people without mutations on these genes. Besides, patients with low expression of ANPEP, GPX3 and GLS genes also survived less time than those with high expression. Hence, we propose that glutathione metabolism and glutathione itself could be good targets to delay or potentially prevent EMT induction in NSCLC cell lines.

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

Abstract: High tumor expression levels of glutamate-cysteine ligase catalytic subunit may be a potential predictor of treatment failure in lung adenocarcinoma patients.

Cited by 24 publications

References 26 publications

The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

Long non-coding RNA LINC00485 acts as a microRNA-195 sponge to regulate the chemotherapy sensitivity of lung adenocarcinoma cells to cisplatin by regulating CHEK1

Analysis of Epithelial-Mesenchymal Transition Metabolism Identifies Possible Cancer Biomarkers Useful in Diverse Genetic Backgrounds

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