Glutaminases regulate glutathione and oxidative stress in cancer

Matés, José M.; Campos-Sandoval, José A.; Santos-Jiménez, Juan de los; Márquez, Javier

doi:10.1007/s00204-020-02838-8

Cited by 50 publications

(39 citation statements)

References 152 publications

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“…Increasing studies have supported that amino acid metabolic genes are vitally important in tumor development. Glutaminase 2 (GLS2) encodes glutaminase, which can induce tumor cells to resist ROS-related apoptosis and enhance drug resistance through p53 mediated transcription ( Matés et al, 2020 ). Serine hydroxymethyltransferase 2 (SHMT2) can be induced by both c-Myc and HIF1α to enhance the ability to resist hypoxia-induced tumor cell death and promote the invasion of various cancers ( Ye et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Zhao

Zhang

Wang

et al. 2021

Front. Cell Dev. Biol.

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Background: Hepatocellular carcinoma (HCC) is the world’s second most deadly cancer, and metabolic reprogramming is its distinguishing feature. Among metabolite profiling, variation in amino acid metabolism supports tumor proliferation and metastasis to the most extent, yet a systematic study on the role of amino acid metabolism-related genes in HCC is still lacking. An effective amino acid metabolism-related prediction signature is urgently needed to assess the prognosis of HCC patients for individualized treatment.Materials and Methods: RNA-seq data of HCC from the TCGA-LIHC and GSE14520 (GPL3921) datasets were defined as the training set and validation set, respectively. Amino acid metabolic genes were extracted from the Molecular Signature Database. Univariate Cox and LASSO regression analyses were performed to build a predictive risk signature. K-M curves, ROC curves, and univariate and multivariate Cox regression were conducted to evaluate the predictive value of this risk signature. Functional enrichment was analyzed by GSEA and CIBERSORTx software.Results: A nine-gene amino acid metabolism-related risk signature including B3GAT3, B4GALT2, CYB5R3, GNPDA1, GOT2, HEXB, HMGCS2, PLOD2, and SEPHS1 was constructed to predict the overall survival (OS) of HCC patients. Patients were separated into high-risk and low-risk groups based on risk scores and low-risk patients had lower risk scores and longer survival time. Univariate and multivariate Cox regression verified that this signature was an independent risk factor for HCC. ROC curves showed that this risk signature can effectively predict the 1-, 2-, 3- and 5-year survival times of patients with HCC. Additionally, prognostic nomograms were established based on the training set and validation set. These genes were closely correlated with the immune regulation.Conclusion: Our study identified a nine-gene amino acid metabolism-related risk signature and built predictive nomograms for OS in HCC. These findings will help us to personalize the treatment of liver cancer patients.

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Section: Introductionmentioning

confidence: 99%

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Zhao

Zhang

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Our differential analysis on the mRNA level showed that GRS, UGT1A6, were upregulated in the Mut group, and they were all downstream genes of the KEAP1/NFE2L2/CUL3 pathway. Glutathione S‐Reductase(GRS) gene, encoding glutathione (GSH) reductase, had a crucial role in the cancer progression and treatment response via the metabolic of glutamine in TME, and Baity et al found that GSR copy number loss is common in LUAD, which might be a biomarker for personalized therapy in the future 63,64 . UDP Glucuronosyltransferase Family 1 Member A6 (UGT1A6) was related to the lipid metabolism by transforming small lipophilic molecules into hydrophilic molecules, and Li et al found that its overexpression in LUAD has relationship with a worse prognosis 65,66 .…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas

et al. 2021

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Objectives To explore the clinical features, molecular characteristics, and immune landscape of lung adenocarcinoma patients with KEAP1/NFE2L2/CUL3 mutations. Methods The multi‐omics data from the GDC‐TCGA LUAD project of The Cancer Genome Atlas (TCGA) database were downloaded from the Xena browser. The estimate of the immune infiltration was implemented by using the GSVA analysis and CIBERSORT. The status of KEAP1/NFE2L2/CUL3 mutation in 50 LUAD samples of our department was detected by using Sanger sequencing, following the relative expression level of differentially expressed genes (DEGs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) was validated by IHC and real‐time quantitative polymerase chain reaction (RT‐qPCR). Results The Kaplan–Meier and multivariable Cox regression analyses demonstrated that KEAP1/NFE2L2/CUL3 mutations had independent prognostic value for OS and PFS in LUAD patients. The differential analysis detected 207 upregulated genes (like GSR/UGT1A6) and 447 downregulated genes (such as PIGR). GO, KEGG, and GSEA analyses demonstrated that DEGs were enriched in glutamate metabolism and the immune response. The constructed ceRNA network shows the linkage of differential lncRNAs and mRNAs. Three hundred and nine somatic mutations were detected, alterations in immune infiltration DNA methylations and stemness scores were also founded between the two groups. Eight mutated LUAD patients were detected by Sanger DNA sequencing in 50 surgical patients. GSR and UGT1A6 were validated to express higher in the Mut group, whereas the expression of PIGR was restrained. Furthermore, the IHC staining conducted on paraffin‐embedded tissue emphasizes the consistency of our result. Conclusion This research implemented the comprehensive analysis of KEAP1/NFE2L2/CUL3 somatic mutations in the LUAD patients. Compared with the wild type of LUAD patients, the Mut group shows a large difference in clinical features, RNA sequence, DNA methylation, and immune infiltrations, indicating complex mechanism oncogenesis and also reveals potential therapeutic targets.

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“…-Superoxide dismutase (SOD): catalyze the breakdown of the superoxide anion into oxygen and hydrogen peroxide [77]; -Catalase (CAT): catalyze the conversion of hydrogen peroxide to water and oxygen, using either an iron or manganese cofactor [78]; -Peroxiredoxins (PRXs): peroxidases that catalyze the reduction in hydrogen peroxide, organic hydroperoxides, as well as peroxynitrite [79]; -Glutathione peroxidases (GPXs): these are enzymes involved in a more complex pathway termed "glutathione system", which includes glutathione, glutathione reductase, glutathione peroxidases, and glutathione S-transferases. Within this series of reactions, glutathione peroxidase catalyzes the breakdown of hydrogen peroxide and organic hydroperoxides [80].…”

Section: Antioxidants As a Defense Mechanism Against Oxidative Stressmentioning

confidence: 99%

Halophilic Carotenoids and Breast Cancer: From Salt Marshes to Biomedicine

Giani

Montoyo-Pujol²,

Peiró³

et al. 2021

Marine Drugs

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Breast cancer is the leading cause of death among women worldwide. Over the years, oxidative stress has been linked to the onset and progression of cancer. In addition to the classical histological classification, breast carcinomas are classified into phenotypes according to hormone receptors (estrogen receptor—RE—/progesterone receptor—PR) and growth factor receptor (human epidermal growth factor receptor—HER2) expression. Luminal tumors (ER/PR-positive/HER2-negative) are present in older patients with a better outcome. However, patients with HER2-positive or triple-negative breast cancer (TNBC) (ER/PR/HER2-negative) subtypes still represent highly aggressive behavior, metastasis, poor prognosis, and drug resistance. Therefore, new alternative therapies have become an urgent clinical need. In recent years, anticancer agents based on natural products have been receiving huge interest. In particular, carotenoids are natural compounds present in fruits and vegetables, but algae, bacteria, and archaea also produce them. The antioxidant properties of carotenoids have been studied during the last years due to their potential in preventing and treating multiple diseases, including cancer. Although the effect of carotenoids on breast cancer during in vitro and in vivo studies is promising, clinical trials are still inconclusive. The haloarchaeal carotenoid bacterioruberin holds great promise to the future of biomedicine due to its particular structure, and antioxidant activity. However, much work remains to be performed to draw firm conclusions. This review summarizes the current knowledge on pre-clinical and clinical analysis on the use of carotenoids as chemopreventive and chemotherapeutic agents in breast cancer, highlighting the most recent results regarding the use of bacterioruberin from haloarchaea.

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Glutaminases regulate glutathione and oxidative stress in cancer

Cited by 50 publications

References 152 publications

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC

Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas

Halophilic Carotenoids and Breast Cancer: From Salt Marshes to Biomedicine

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