GLUL Promotes Cell Proliferation in Breast Cancer

Wang, Yanyan; Fan, Shao‐Hua; Lü, Jun; Zhang, Zifeng; Wu, Dongmei; Wu, Zhi‐Yong; Zheng, Yuxin

doi:10.1002/jcb.25775

Cited by 32 publications

(37 citation statements)

References 37 publications

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“…Meanwhile, we found an increased GLUL expression in all subtypes of lung cancer. Elevated GLUL has already been found in many other types of cancers (Christa et al, 1994;Rosati et al, 2013;Wang et al, 2016). Our results indicate that GLUL may also play some important roles in lung cancer progression.…”

Section: Discussionsupporting

confidence: 76%

“…It is majorly expressed in normal muscle tissue, adipose tissue, the brain, and the liver to balance ammonia, glutamate, and glutamine levels in those organs and the whole body (Curthoys and Watford, 1995). The expression of GLUL is relatively low in other normal tissues but was found to be elevated in cancer cells from the liver, brain, and breasts (Christa et al, 1994;Rosati et al, 2013;Wang et al, 2016). Since GLUL is the only glutamine synthetase in the human body, most studies focus on its functions in benefiting cancer cells' survival and growth under glutamine restriction.…”

Section: Introductionmentioning

confidence: 99%

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Glutamate-ammonia ligase promotes lung cancer cell growth through an enzyme-independent upregulation of CaMK2G under a glutamine-sufficient condition

Zhao

Zeng

Hou

2019

Preprint

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Glutamate-ammonia ligase (GLUL) is highly expressed in many cancer cells. Synthesizing glutamine by its enzyme function has been found to be important for supporting cancer cell survival and growth under glutamine restriction. However, GLUL's functions under a glutamine-sufficient condition still have not been uncovered. Here we find that GLUL is highly expressed in lung cancer cells and provides survival and growth advantages under both glutamine restriction and adequacy conditions. Knocking down GLUL can block lung cancer cell growth in an enzyme-independent way when glutamine is sufficient.Mechanistically, GLUL regulates Calcium/Calmodulin Dependent Protein Kinase II Gamma (CaMK2G) expression at the transcription level, and CaMK2G is a major mediator in controlling cell growth under GLUL. The transcriptional regulation of CaMK2G is partially mediated by SMAD4. Our data unveil a new enzyme-independent function of GLUL in lung cancer cells under a glutamine-sufficient condition.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Glutamate-ammonia ligase promotes lung cancer cell growth through an enzyme-independent upregulation of CaMK2G under a glutamine-sufficient condition

Zhao

Zeng

Hou

2019

Preprint

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“…We found higher expression of GLUL in the breast cancer patients was associated with larger tumor size and higher level of HER2 expression . Great interest in GLUL research has led to discovery of several GLUL inhibitors.…”

Section: Discussionmentioning

confidence: 74%

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

Fan

Wang

Zhang

et al. 2018

J of Cellular Biochemistry

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Glutamate-ammonia ligase (GLUL), which is also called GS (glutamine synthetase), is the enzyme that catalyzes the synthesis of glutamine from glutamate and ammonia in an ATP-dependent reaction. Here, we found higher expression of GLUL in the ovarian cancer patients was associated with worse disease-free survival (DFS) and overall survival (OS). In addition, GLUL was heterogeneously expressed in various ovarian cancer cells. The mRNA and protein expression levels of GLUL in NIH:OVCAR-3 and ES-2 cells were obviously higher than that in the other types of ovarian cancer cells. Knockdown of GLUL in NIH:OVCAR-3 or ES-2 cells could significantly decrease the proliferation ability. Furthermore, GLUL knockdown markedly inhibited the p38 MAPK signaling pathway in NIH:OVCAR-3 or ES-2 cells. Our findings suggest that decreasing expression of GLUL may be a new approach that can be used for ovarian cancer treatment.

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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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GLUL Promotes Cell Proliferation in Breast Cancer

Cited by 32 publications

References 37 publications

Glutamate-ammonia ligase promotes lung cancer cell growth through an enzyme-independent upregulation of CaMK2G under a glutamine-sufficient condition

Glutamate-ammonia ligase promotes lung cancer cell growth through an enzyme-independent upregulation of CaMK2G under a glutamine-sufficient condition

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

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

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