Dysregulation of glutaminase and glutamine synthetase in cancer

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

doi:10.1016/j.canlet.2019.09.011

Cited by 133 publications

(110 citation statements)

References 111 publications

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“…Tumor cells adopt a unique metabolic strategy by coupling aerobic glycolysis and glutaminolysis [18,37,38]. GLUT1 and PKM2 play a key role in glucose uptake and aerobic glycolysis [26].…”

Section: Discussionmentioning

confidence: 99%

“…GLUT1 and PKM2 play a key role in glucose uptake and aerobic glycolysis [26]. Whereas SLC1A5 and SLC7A5 transport extracellular glutamine into the cells, and glutaminase metabolizes glutamine to glutamate for the completion of the citric acid cycle, GSH synthesis, and pentose phosphate pathway [18,38]. An additional study has shown that glutamine is beneficial to hepatic glucose homeostasis in obese mice [39].…”

Section: Discussionmentioning

confidence: 99%

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Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition

Wang

Chen

et al. 2020

Cells

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Obesity is associated with a wide range of chronic diseases, including cancer. It has been noted that the integration of metabolic mechanisms in obese patients may predispose them to suffer from cancer incidence and its progression. Thus, a better understanding of metabolic alterations in obesity, along with the development of feasible therapeutic approaches for intervention, are theoretically relevant to the prevention and treatment of cancer malignancy. Using a syngeneic tumor model involving Lewis Lung Carcinoma (LLC) cells and C57BL/6 mice fed with a high fat diet, obesity was found to be associated with dysregulated glucose and glutamine metabolism, inflammation, along with platelet activation and the promotion of tumor growth. Tumor-bearing lowered glucose levels while moderately increasing inflammation, platelet activation, and glutamine levels. The antiplatelet drug aspirin, mitigated tumor growth in obese mice, paralleled by a decrease in systemic glucose, insulin, inflammation, platelet activation, glutamine and tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets, and leukocyte molecules. The anti- and pro-cell proliferation, aerobic glycolysis, and glutaminolysis effects of aspirin and glutamine were further demonstrated in a LLC cell study. Although there remains limitations to our experiments, glucose and glutamine metabolism are proposed targets for the anticancer effects of aspirin.

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“…Tumor cells adopt a unique metabolic strategy by coupling aerobic glycolysis and glutaminolysis [18,37,38]. GLUT1 and PKM2 play a key role in glucose uptake and aerobic glycolysis [26].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition

Wang

Chen

et al. 2020

Cells

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“…Previous studies have suggested that glucose and glutamine are the two main energy sources required for the rapid proliferation of tumor cells [20,21]. Notably, some cancers seem to prefer aerobic glycolysis [22.23], others rely more on glutaminolysis pathway [24] Additionally, there are also some cancers tend to a combination of such two metabolic pathways [25]. Given the important role of glucose and glutamine in cell proliferation and survival, it is of great signi cance to clarify the relationship between glucose metabolism and glutaminolysis in HCC cells.…”

Section: Discussionmentioning

confidence: 99%

Glutamate dehydrogenase 1 mediated glutaminolysis sustains HCC cells proliferation and survival under glucose deprivation

Zhou¹,

Yu²,

Cheng³

et al. 2020

Preprint

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Background: It is generally believed that tumor cells could sustain its proliferation and survival under different nutrient status according to a so-called metabolic flexibility. How the metabolic flexibility of glutamine metabolism of HCC cells behaves under different glucose conditions has not yet been fully elucidated. In this study, we investigated how the glutamine metabolism modulate the proliferation and survival of HCC cells in response to different glucose conditions and explored the underlying molecular mechanism.Methods: Two cell lines SK-Hep-1 and PLC/PRF/5 were used to evaluate the glutamine addiction of HCC cells. Then, the cells were cultivated in high glucose medium (25mM glucose) and low glucose medium (1.0 mM glucose), respectively, to investigate whether glutaminolysis changed in response to different glucose levels. And, the underlying mechanism of glutamate dehydrogenase 1 (GDH1) sustaining HCC cells survival under glucose deprivation was explored. Additionally, the underlying correlation of GDH1 and glutamate–oxaloacetate transaminase 1 (GOT1) in glucose -poor HCC tissue was investigated.Results: HCC cells were addicted to glutamine. The glutaminolysis of HCC cells was different in response to different glucose conditions. That is, glutamate transaminases GOT1 involved glutamine metabolism played a dominant role in regulating cell growth when glucose was sufficient, while deaminase GDH1 mediated glutaminolysis became dominant when glucose was limited. Mechanically, low-glucose treated HCC cells could induce an elevated expression of GDH1 to supplement the TCA cycles in respond to glucose deprivation. Additionally, we further uncovered an underlying negative association between GDH1 and GOT1 in HCC tissues with decreased glucose levelsConclusions: GDH1 mediated pathway played a leading role in maintaining cell proliferation and survival under low glucose condition. By contrast, GOT1 mediated pathway was activated under high glucose condition. Mechanically, highly expressed GDH1 could drive the TCA cycle in response to glucose deprivation. Besides, there was a potential negative correlation between GDH1 and GOT1 in glucose-poor HCC tissues.

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“…Increased metabolism of Gln, of which the first step is catabolized by glutaminase (GA; EC 3.5.1.2), is a hallmark of cancer. Therefore, GA is a potential therapeutic target for different cancer types [41].…”

Section: Inhibitors Of Glutaminase (Ga)mentioning

confidence: 99%

Thiadiazole derivatives as anticancer agents

Szeliga

2020

Pharmacol. Rep

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In spite of substantial progress made toward understanding cancer pathogenesis, this disease remains one of the leading causes of mortality. Thus, there is an urgent need to develop novel, more effective anticancer therapeutics. Thiadiazole ring is a versatile scaffold widely studied in medicinal chemistry. Mesoionic character of this ring allows thiadiazole-containing compounds to cross cellular membrane and interact strongly with biological targets. Consequently, these compounds exert a broad spectrum of biological activities. This review presents the current state of knowledge on thiadiazole derivatives that demonstrate in vitro and/or in vivo efficacy across the cancer models with an emphasis on targets of action. The influence of the substituent on the compounds’ activity is depicted. Furthermore, the results from clinical trials assessing thiadiazole-containing drugs in cancer patients are summarized.

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Dysregulation of glutaminase and glutamine synthetase in cancer

Cited by 133 publications

References 111 publications

Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition

Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition

Glutamate dehydrogenase 1 mediated glutaminolysis sustains HCC cells proliferation and survival under glucose deprivation

Thiadiazole derivatives as anticancer agents

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