High expression of glutamate‐ammonia ligase is associated with unfavorable prognosis in patients with ovarian cancer

Fan, Shao‐Hua; Wang, Yanyan; Zhang, Zifeng; Lü, Jun; Wu, Zhi‐Yong; Shan, Qun; Sun, Chunhui; Wu, Dongmei; Li, Mengqiu; Sheng, Ning; Xie, Ying; Zheng, Yuxin

doi:10.1002/jcb.26797

Cited by 27 publications

(28 citation statements)

References 30 publications

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“…Glutamate is another important substrate for oxidative phosphorylation in tumor cells with OXPHOS activity. A higher expression of glutamine synthetase in ovarian cancer patients has been shown to be associated with a worse disease-free and overall survival (32). Glutamate metabolic programming has been reported to play a role in the metastasis of many tumors (17).…”

Section: Discussionmentioning

confidence: 99%

PAX2 promotes epithelial ovarian cancer progression involving fatty acid metabolic reprogramming

et al. 2020

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Ovarian cancer is the fifth most common type of cancer afflicting women and frequently presents at a late stage with a poor prognosis. While paired box 2 (PAX2) expression is frequently lost in high-grade serous ovarian cancer, it is expressed in a subset of ovarian tumors and may play a role in tumorigenesis. This study investigated the expression of PAX2 in ovarian cancer. The expression of PAX2 in a murine allograft model of ovarian cancer, the RM model, led to a more rapidly growing cell line both in vitro and in vivo. This finding was in accordance with the shorter progression-free survival observed in patients with a higher PAX2 expression, as determined in this study cohort by immunohistochemistry. iTRAQ-based proteomic profiling revealed that proteins involved in fatty acid metabolism and oxidative phosphorylation were found to be upregulated in RM tumors expressing PAX2. The expression of two key fatty acid metabolic genes was also found to be upregulated in PAX2-expressing human ovarian cancer samples. The analysis of existing datasets also indicated that a high expression of key enzymes in fatty acid metabolism was associated with a shorter progression-free survival time in patients with serous ovarian cancer. Thus, on the whole, the findings of this study indicate that PAX2 may promote ovarian cancer progression, involving fatty acid metabolic reprograming.

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Section: Discussionmentioning

confidence: 99%

PAX2 promotes epithelial ovarian cancer progression involving fatty acid metabolic reprogramming

et al. 2020

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“…Glycine has also been suggested to promote innate immune responses (Schaumann et al, ). Glutamate‐ammonia ligase (GLUL), which is also known as glutamine synthetase (GS), is the enzyme that catalyses the synthesis of glutamine from glutamate and ammonia in an ATP‐dependent reaction (Fan et al, ), and glutamine is important for the immune and gut development of pigs (Ewaschuk, Murdoch, Johnson, Madsen, & Field, ; Johnson, Ball, Baracos, & Field, ). Indoleamine 2,3‐dioxygenase (IDO1) is the first rate‐limiting enzyme of tryptophan catabolism through the kynurenine pathway, which is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+).…”

Section: Discussionmentioning

confidence: 99%

Dietary Clostridium butyricum supplementation modifies significantly the liver transcriptomic profile in weaned piglets

Qiao

2020

Animal Physiology Nutrition

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The addition of probiotics in swine nutrition is known to positively influence both health and growth. The current study investigates differences in the hepatic transcriptome profiles between weaned piglets supplemented with Clostridium butyricum (C. butyricum) and control animals that received no probiotic. The liver is an important metabolic organ that plays a critical role in oxidizing triglycerides for energy production, lipid synthesis and degradation, as well as immune regulation in animals. RNA‐Seq analysis was carried out on total RNA harvested from the liver of piglets fed with (n = 3) or without (n = 3) 5 × 105 C. butyricum CFU/g. Compared to the control piglets, 588 of the genes examined (352 up‐regulated and 236 down‐regulated) were significantly differentially expressed at a fold change > 2 and p < .05 in animals fed with C. butyricum. Quantitative real‐time reverse transcription PCR (qRT‐PCR) analysis was further used to validate the microarray expression results for 28 genes tested. The functional annotation analyses revealed several genes, processes and pathways with putative involvement in piglet growth and performance. Feeding swine with 5 × 105 C. butyricum CFU/g appears to reinforce their immune status as well as foster the cell cycle and improve the metabolism of carbohydrates, lipids and amino acids. This study provides valuable information about the expression profiles of mRNAs in piglet liver and in‐depth functional investigations of these mRNAs that could provide new insights into the molecular networks of growth, immune responses and nutrient metabolism in the porcine liver.

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“…Furthermore, a mouse NSCLC model did not catabolize glutamine through glutaminolysis at all but depended solely on glucose-derived carbon flux [37]. Several studies have revealed a prognostic value of GLUL expression in different cancer types [21][22][23][24]. Further, the ablation of GLUL in SK-BR-3 cells reduced their proliferation [22].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, GLUL could be important beyond its main catalytic activity during tumor growth [20]. Increased GLUL expression has been reported as an early marker of hepatocellular carcinoma [21], promoting breast cancer cell proliferation [22], and also found to be an unfavorable prognostic marker in patients with glioblastoma multiforme (GBM) and ovarian cancer [23,24]. Our group has previously identified reduced GLUL transcription to be associated with resistance to the chemotherapeutic agent daunorubicin in clones of acute lymphoblastic leukemia (ALL) [14].…”

Section: Introductionmentioning

confidence: 99%

GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism

Magesh

Kumar

Khaja

et al. 2019

Cancers

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Glutamate-ammonia ligase (GLUL) is important for acid-base homeostasis, ammonia detoxification, cell signaling, and proliferation. Here, we reported that GLUL ablation conferred resistance to several anticancer drugs in specific cancer cell lines while leaving other cell lines non-resistant to the same drugs. To understand the biochemical mechanics supporting this drug resistance, we compared drug-resistant GLUL knockout (KO) A549 non-small-cell lung carcinoma (NSCLC) cells with non-resistant GLUL KO H1299 NSCLC cells and found that the resistant A549 cells, to a larger extent, depended on exogenous glucose for proliferation. As GLUL activity is linked to the tricarboxylic acid (TCA) cycle via reversed glutaminolysis, we probed carbon flux through both glycolysis and TCA pathways by means of 13C5 glutamine, 13C5 glutamate, and 13C6 glucose tracing. We observed increased labeling of malate and aspartate in A549 GLUL KO cells, whereas the non-resistant GLUL KO H1299 cells displayed decreased 13C-labeling. The malate and aspartate shuttle supported cellular NADH production and was associated with cellular metabolic fitness. Inhibition of the malate-aspartate shuttle with aminooxyacetic acid significantly impacted upon cell viability with an IC50 of 11.5 μM in resistant GLUL KO A549 cells compared to 28 μM in control A549 cells, linking resistance to the malate-aspartate shuttle. Additionally, rescuing GLUL expression in A549 KO cells increased drug sensitivity. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malate-aspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to escape drug pressure.

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High expression of glutamate‐ammonia ligase is associated with unfavorable prognosis in patients with ovarian cancer

Cited by 27 publications

References 30 publications

PAX2 promotes epithelial ovarian cancer progression involving fatty acid metabolic reprogramming

PAX2 promotes epithelial ovarian cancer progression involving fatty acid metabolic reprogramming

Dietary Clostridium butyricum supplementation modifies significantly the liver transcriptomic profile in weaned piglets

GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism

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