Glutamine deprivation triggers NAGK-dependent hexosamine salvage
Year: 2021
Type: article
Abstract: 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.
Source: eLife
DOI: 10.7554/elife.62644
Authors: Sydney L. 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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Training in Tumor Virology, Training Program in Cell and Molecular Biology, Role of acetyl-CoA in linking cancer cell metabolism and epigenetics, Role of the hexosamine biosynthesis pathway in pancreatic cancer., G5213607146, Investigating paradoxical YAP activation as an emergent limitation to Cu chelation therapy in BRAF V600E-driven melanoma, Leveraging polyamine metabolic stress as a novel therapy for prostate cancer, Defining an acetyl-CoA sensing mechanism as a form of inter-organelle communication in cancer, Center of Excellence in Environmental Toxicology, Mitogenic and Oncogenic Regulation of ERK/RSK Signaling, Abramson Cancer Center Support Grant, G985502297
OpenAlex ID: W3215354274