Glutamine deprivation triggers NAGK-dependent hexosamine salvage

Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the...

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Autores principales:	Sydney Campbell, Clementina Mesaros, Luke Izzo, Hayley Affronti, Michael Noji, Bethany E Schaffer, Tiffany Tsang, Kathryn Sun, Sophie Trefely, Salisa Kruijning, John Blenis, Ian A Blair, Kathryn E Wellen
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	hexosamine pancreatic cancer N-acetylglucosamine kinase glutamine Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5ce0bca35ac845fba57a2e6f6f790030
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spelling	oai:doaj.org-article:5ce0bca35ac845fba57a2e6f6f7900302021-11-30T09:26:29ZGlutamine deprivation triggers NAGK-dependent hexosamine salvage10.7554/eLife.626442050-084Xe62644https://doaj.org/article/5ce0bca35ac845fba57a2e6f6f7900302021-11-01T00:00:00Zhttps://elifesciences.org/articles/62644https://doaj.org/toc/2050-084XTumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the HBP as a promising therapeutic target in pancreatic ductal adenocarcinoma (PDA). The HBP requires both glucose and glutamine for its initiation. The PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how nutrient limitation impacts hexosamine synthesis. Here, we identify that glutamine limitation in PDA cells suppresses de novo hexosamine synthesis but results in increased free GlcNAc abundance. GlcNAc salvage via N-acetylglucosamine kinase (NAGK) is engaged to feed UDP-GlcNAc pools. NAGK expression is elevated in human PDA, and NAGK deletion from PDA cells impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.Sydney CampbellClementina MesarosLuke IzzoHayley AffrontiMichael NojiBethany E SchafferTiffany TsangKathryn SunSophie TrefelySalisa KruijningJohn BlenisIan A BlairKathryn E WelleneLife Sciences Publications Ltdarticlehexosaminepancreatic cancerN-acetylglucosamine kinaseglutamineMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hexosamine pancreatic cancer N-acetylglucosamine kinase glutamine Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	hexosamine pancreatic cancer N-acetylglucosamine kinase glutamine Medicine R Science Q Biology (General) QH301-705.5 Sydney Campbell Clementina Mesaros Luke Izzo Hayley Affronti Michael Noji Bethany E Schaffer Tiffany Tsang Kathryn Sun Sophie Trefely Salisa Kruijning John Blenis Ian A Blair Kathryn E Wellen Glutamine deprivation triggers NAGK-dependent hexosamine salvage
description	Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the HBP as a promising therapeutic target in pancreatic ductal adenocarcinoma (PDA). The HBP requires both glucose and glutamine for its initiation. The PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how nutrient limitation impacts hexosamine synthesis. Here, we identify that glutamine limitation in PDA cells suppresses de novo hexosamine synthesis but results in increased free GlcNAc abundance. GlcNAc salvage via N-acetylglucosamine kinase (NAGK) is engaged to feed UDP-GlcNAc pools. NAGK expression is elevated in human PDA, and NAGK deletion from PDA cells impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.
format	article
author	Sydney Campbell Clementina Mesaros Luke Izzo Hayley Affronti Michael Noji Bethany E Schaffer Tiffany Tsang Kathryn Sun Sophie Trefely Salisa Kruijning John Blenis Ian A Blair Kathryn E Wellen
author_facet	Sydney Campbell Clementina Mesaros Luke Izzo Hayley Affronti Michael Noji Bethany E Schaffer Tiffany Tsang Kathryn Sun Sophie Trefely Salisa Kruijning John Blenis Ian A Blair Kathryn E Wellen
author_sort	Sydney Campbell
title	Glutamine deprivation triggers NAGK-dependent hexosamine salvage
title_short	Glutamine deprivation triggers NAGK-dependent hexosamine salvage
title_full	Glutamine deprivation triggers NAGK-dependent hexosamine salvage
title_fullStr	Glutamine deprivation triggers NAGK-dependent hexosamine salvage
title_full_unstemmed	Glutamine deprivation triggers NAGK-dependent hexosamine salvage
title_sort	glutamine deprivation triggers nagk-dependent hexosamine salvage
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/5ce0bca35ac845fba57a2e6f6f790030
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Glutamine deprivation triggers NAGK-dependent hexosamine salvage

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