The hexosamine pathway and coat complex II promote malignant adaptation to nutrient scarcity.

Helena Dragic, Audrey Barthelaix, Cédric Duret, Simon Le Goupil, Hadrien Laprade, Sophie Martin, Sabine Brugière, Yohann Couté, Christelle Machon, Jerome Guitton, Justine Rudewicz, Paul Hofman, Serge Lebecque, Cedric Chaveroux, Carole Ferraro-Peyret, Toufic Renno, Serge N Manié

Journal: Life science alliance 2022;5(7):e202101334

PMID: 35396334

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Abstract

The glucose-requiring hexosamine biosynthetic pathway (HBP), which produces UDP-N-acetylglucosamine for glycosylation reactions, promotes lung adenocarcinoma (LUAD) progression. However, lung tumor cells often reside in low-nutrient microenvironments, and whether the HBP is involved in the adaptation of LUAD to nutrient stress is unknown. Here, we show that the HBP and the coat complex II (COPII) play a key role in cell survival during glucose shortage. HBP up-regulation withstood low glucose-induced production of proteins bearing truncated -glycans, in the endoplasmic reticulum. This function for the HBP, alongside COPII up-regulation, rescued cell surface expression of a subset of glycoproteins. Those included the epidermal growth factor receptor (EGFR), allowing an EGFR-dependent cell survival under low glucose in anchorage-independent growth. Accordingly, high expression of the HBP rate-limiting enzyme GFAT1 was associated with wild-type EGFR activation in LUAD patient samples. Notably, HBP and COPII up-regulation distinguished LUAD from the lung squamous-cell carcinoma subtype, thus uncovering adaptive mechanisms of LUAD to their harsh microenvironment.

Address: Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre National de la Recherche Scientifique (CNRS) 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.; Institute for Regenerative Medecine and Biotherapy (IRBM), Université de Montpellier, INSERM, Montpellier, France.; Inserm U1242, Centre de Lutte Contre le Cancer Eugène Marquis, Université de Rennes, Rennes, France.; Université Grenoble Alpes, INSERM, Commissariat à l'Energie Atomique (CEA), Unite Mixte de Recherche (UMR) BioSanté U1292, CNRS, CEA, FR2048, Grenoble, France.; Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre National de la Recherche Scientifique (CNRS) 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.; U Hospices Civils of Lyon, Biochemistry and Pharmaco-toxicology Laboratory, Lyon Sud Hospital, Lyon, France.; Bordeaux Bioinformatics Center, CBiB, University of Bordeaux, Bordeaux, France.; Laboratory of Clinical and Experimental Pathology, Federation Hospitalo-Universitaire (FHU) OncoAge and BB-0033-00025, Nice University Hospital, IRCAN Antoine Lacassagne Center, Côte d'Azur University, Nice, France.; Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre National de la Recherche Scientifique (CNRS) 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.; Hospices Civils de Lyon, Biopathology of Tumours, GHE Hospital, Bron, France.; Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Centre National de la Recherche Scientifique (CNRS) 5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France [email protected].; Inserm U1242, Centre de Lutte Contre le Cancer Eugène Marquis, Université de Rennes, Rennes, France.

DOI: 10.26508/lsa.202101334

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Miscellaneous:

https://assays.cancer.gov/CPTAC-802

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-EGFR-8

MeSH Terms: ErbB Receptors, Glucose, Glycosylation, Hexosamines, Humans, Nutrients