Mutation of the Nrf2 gene in non-small cell lung cancer

Hu, Yi; Ju, Yanfang; Lin, Dongmei; Wang, Zhikuan; Huang, Yurong; Zhang, Sujie; Wu, Chao; Jiao, Shunchang

doi:10.1007/s11033-011-1266-4

Cited by 31 publications

(25 citation statements)

References 17 publications

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“…Sequencing experiments revealed that the A549 cell line harbors a mutation (glycine 333 to cysteine) in the Kelch domain and that the H460 cell line harbors a mutation (aspartic acid 236 to histidine) in the intervention region of KEAP1. No mutations in exon 2 of the NRF2 gene, the site associated with most NRF2 mutations [37], have been identified in sequencing analysis. We observed increased basal levels of NRF2 downstream target genes in the NSCLC cell lines harboring KEAP1 mutations compared with the wild-type KEAP1 NSCLC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Modification of platinum sensitivity by KEAP1/NRF2 signals in non-small cell lung cancer

Tian

Liu

et al. 2016

J Hematol Oncol

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BackgroundThe objective of this study was to evaluate the effect of platinum-based drugs on nuclear-factor erythroid2 like 2 (NRF2) signaling in non-small cell lung cancer cell lines with or without Kelch-like ECH-associated protein 1 (KEAP1) mutations and to determine the role of NRF2 and KEAP1 on platinum-based drug treatment.MethodsWe used real-time PCR to assess relative mRNA expression and used western blotting and immunofluorescence assays to assess protein expression. Small interfering RNA and shuttle plasmids were used to modulate the expression of NRF2, wild-type KEAP1, and mutant KEAP1. Drug sensitivity to platinum-based drugs was evaluated with Cell Count Kit-8.ResultsWe found that platinum-based therapies modified the NRF2 signaling pathway differently in KEAP1-mutated non-small cell lung cancer (NSCLC) cell lines compared with wild-type KEAP1 cell lines. The reactive degree of NRF2 signaling also varies between nedaplatin and cisplatin. The modification of NRF2 or KEAP1 expression in NSCLC cell lines disrupted downstream gene expression and cell sensitivity to platinum-based drugs. Finally, gene expression data retrieved from The Cancer Genome Atlas (TCGA) consortium indicated that KEAP1 mutation significantly affects NRF2 signaling activity in patients with NSCLC.ConclusionsOur findings suggest that NRF2 signaling plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and provides a rationale for using NRF2 as a specific biomarker for predicting which patients will be most likely to benefit from platinum-based treatment.

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Section: Discussionmentioning

confidence: 99%

Modification of platinum sensitivity by KEAP1/NRF2 signals in non-small cell lung cancer

Tian

Liu

et al. 2016

J Hematol Oncol

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“…Based on these two major roles, we aimed to ascertain whether GSTP1 also affects cancer prognosis in ESCC. The second reason is that GSTP1 expression is partially regulated by the Nrf2 gene, which is a transcriptional factor that is frequently upregulated in lung cancer, esophageal cancer and several other squamous cell carcinomas (29,30). In ESCC cell lines and primary samples, mutations in Nrf2 are frequently reported (31).…”

Section: Discussionmentioning

confidence: 99%

Significance of GSTP1 for predicting the prognosis and chemotherapeutic efficacy in esophageal squamous cell carcinoma

et al. 2013

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Abstract. Glutathione S-transferases (GSTs) have been reported to be activated in several types of cancers, including esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate whether GSTP1 protein expression is a useful predictor of the clinical outcome or drug resistance in ESCC. Immunohistochemistry was conducted with 75 ESCC resected specimens using a monoclonal antibody against GSTP1. The patients were divided into two groups according to the degree of GSTP1 staining, and the relationship between the GSTP1 level and the clinicopathological features was examined. Seventy-five patients were divided into low (grade 1, n=36) and high (grade 2, n=39) GSTP1 expression groups. The overall survival was significantly worse in the grade 2 patients than in the grade 1 patients (5-year survival rate, 78.5 vs. 51.2%; p=0.027). Cox proportional hazard analysis revealed that macroscopic type 3 or 4 disease (p=0.001), lymph node metastasis (p=0.010), and high GSTP1 expression (p=0.029) were independent predictors of a poor prognosis. With regard to the subgroup analysis among the 31 patients undergoing adjuvant chemotherapy, the grade 2 patients had a worse prognosis than did the grade 1 patients (5-year survival rate, 45.0 vs. 81.8%; p=0.081). This tendency was not observed in the subgroup without adjuvant chemotherapy (5-year survival rate, 51.7 vs. 59.9%; p=0.979). In conclusion, the GSTP1 expression is a good predictor of prognosis, and it may be closely related to the chemotherapeutic efficacy of 5-FU plus cisplatin in ESCC patients.

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“…Somatic mutations identified in the NRF2 gene of human cancer patients are located within the 5= region of the gene encoding the N-terminal Neh2 domain (3), especially in proximity to the DLG and ETGE motifs. We surveyed the current literature (32,33) and the mutation database of the Catalogue of Somatic Mutations in Cancer at the Sanger Institute (http://www.sanger.ac.uk/cosmic) (34) and compiled the somatic mutations shown in Fig. 1.…”

Section: Somatic Mutations Encompassing Nrf2-dlg In Human Cancersmentioning

confidence: 99%

Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1

Fukutomi

Takagi

Mizushima

et al. 2014

Molecular and Cellular Biology

213

243

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cTranscription factor Nrf2 (NF-E2-related factor 2) coordinately regulates cytoprotective gene expression, but under unstressed conditions, Nrf2 is degraded rapidly through Keap1 (Kelch-like ECH-associated protein 1)-mediated ubiquitination. Nrf2 harbors two Keap1-binding motifs, DLG and ETGE. Interactions between these two motifs and Keap1 constitute a key regulatory nexus for cellular Nrf2 activity through the formation of a two-site binding hinge-and-latch mechanism. In this study, we determined the minimum Keap1-binding sequence of the DLG motif, the low-affinity latch site, and defined a new DLGex motif that covers a sequence much longer than that previously defined. We have successfully clarified the crystal structure of the Keap1-DC-DLGex complex at 1.6 Å. DLGex possesses a complicated helix structure, which interprets well the human-cancer-derived loss-of-function mutations in DLGex. In thermodynamic analyses, Keap1-DLGex binding is characterized as enthalpy and entropy driven, while Keap1-ETGE binding is characterized as purely enthalpy driven. In kinetic analyses, Keap1-DLGex binding follows a fast-association and fast-dissociation model, while Keap1-ETGE binding contains a slow-reaction step that leads to a stable conformation. These results demonstrate that the mode of DLGex binding to Keap1 is distinct from that of ETGE structurally, thermodynamically, and kinetically and support our contention that the DLGex motif serves as a converter transmitting environmental stress to Nrf2 induction as the latch site.

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Mutation of the Nrf2 gene in non-small cell lung cancer

Cited by 31 publications

References 17 publications

Modification of platinum sensitivity by KEAP1/NRF2 signals in non-small cell lung cancer

Modification of platinum sensitivity by KEAP1/NRF2 signals in non-small cell lung cancer

Significance of GSTP1 for predicting the prognosis and chemotherapeutic efficacy in esophageal squamous cell carcinoma

Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1

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