Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism

Bott, A. J., Shen, J., Tonelli, C., Zhan, L., Sivaram, N., Jiang, Y. P., Yu, X., Bhatt, V., Chiles, E., Zhong, H., Maimouni, S., Dai, W., Velasquez, S., Pan, J. A., Muthalagu, N., Morton, J., Anthony, T. G., Feng, H., Lamers, W. H., Murphy, D. J., Guo, J. Y., Jin, J., Crawford, H. C., Zhang, L., White, E., Lin, R. Z., Su, X., Tuveson, D. A., Zong, W. X. (October 2019) Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism. Cell Rep, 29 (5). 1287-1298.e6.

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URL: https://www.ncbi.nlm.nih.gov/pubmed/31665640

DOI: 10.1016/j.celrep.2019.09.056

Abstract

Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to alpha-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of Kras(G12D)-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function organism description > animal > mammal organs, tissues, organelles, cell types and functions > organs types and functions > metabolism organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent
CSHL Authors:	Tuveson, David A. Tonelli, Claudia
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Tuveson lab CSHL Cancer Center Shared Resources > Animal Shared Resource
Depositing User:	Matthew Dunn
Date:	29 October 2019
Date Deposited:	08 Nov 2019 16:47
Last Modified:	01 Feb 2024 20:42
PMCID:	PMC6886125
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38674

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