IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3

Reid, Michael A.; Lowman, Xazmin H.; Pan, Min; Tran, Trac D.; Warmoes, Marc O.; Gabra, Mari B. Ishak; Yang, Ying; Locasale, Jason W.; Kong, Mei

doi:10.1101/gad.287235.116

Cited by 48 publications

(50 citation statements)

References 64 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results suggest that GLUL's function is limited under glutamine deprivation in those lung cancer cells. In fact, cancer cells can utilize many other ways to sustain cell proliferation and survival when deprived of glutamine (Cheng et al, 2011;Reid et al, 2016).…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…As examples, one study found that the requirements for glutamine undergo changes upon transition from monolayer culture to anchorage-independent culture [7], and another study found that glutamine catabolism was not required for tumorigenesis in vivo in some mouse models, which led to the conclusion that glutamine metabolism may not have a role in cancer [13]. Nevertheless, numerous other studies have provided compelling evidence that a requirement for glutamine catabolism indeed exists in many in vivo settings [10, 14–21]. In this review, we discuss these seemingly contradictory recent findings in detail and explain the factors underlying the heterogeneity of glutamine metabolism in cancer.…”

Section: Metabolic Reprogramming In Cancermentioning

confidence: 99%

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

et al. 2017

Self Cite

View full text Add to dashboard Cite

Reliance on glutamine has long been considered a hallmark of cancer cell metabolism. However, some recent studies have challenged this notion in vivo, prompting a need for further clarifications on the role of glutamine metabolism in cancer. We find that there is ample evidence of an essential role for glutamine in tumors and that a variety of factors, including tissue type, the underlying cancer genetics, the tumor microenvironment and other variables such as diet and host physiology collectively influence the role of glutamine in cancer. Thus the requirements for glutamine in cancer are overall highly heterogeneous. In this review, we discuss the implications both for basic science and for targeting glutamine metabolism in cancer therapy.

show abstract

“…Glutamine is required for cell survival (16)(17)(18)(19), and its loss induced cell death ( Fig. 1A; Supplementary Fig.…”

Section: Requirement Of Glutamine-nitrogen For Cell Survivalmentioning

confidence: 99%

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

Wang

Bai

Ruan

et al. 2018

Preprint

View full text Add to dashboard Cite

Under hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.Significance: Tumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.

show abstract

IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3

Cited by 48 publications

References 64 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

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

Contact Info

Product

Resources

About