Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism

Bott, A. J. et al. (2019) Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism. Cell Reports, 29(5), 1287-1298.e6. (doi: 10.1016/j.celrep.2019.09.056) (PMID:31665640) (PMCID:PMC6886125)

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Abstract

Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-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 KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.

Item Type:Articles
Additional Information:The study was supported by NIH grants F99CA212445 (to A.J.B.); R01CA224550, R01CA129536, R01CA232246, R21CA205172 (to W.X.Z.); R01CA215059 (to H.F.); R01DK109714 (to T.G.A.); 5P30CA45508 (including the Animal and Animal and Tissue Engineering Shared Resource), 5P50CA101955, P20CA192996, U10CA180944, U01CA210240, U01CA224013, 1R01CA188134, and R01CA190092 (to D.A.T.); K22CA190521 (to J.Y.G.); and LCRF (to J.Y.G.). We are also grateful for support from the Lustgarten Foundation (where D.A.T. is a distinguished scholar), the Northwell Health Affiliation (to D.A.T.), and American Italian Cancer Foundation (to C.T.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morton, Professor Jen and Murphy, Professor Daniel
Authors: 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., and Zong, W.-X.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Published Online:30 October 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cell Reports 29(5): 1287-1298.e6
Publisher Policy:Reproduced under a Creative Commons License

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