Multitranscript analysis reveals an effect of 2-deoxy-d-glucose on gene expression linked to unfolded protein response and integrated stress response in primary human monocytes and monocyte-derived macrophages

ABSTRACT: Background: Glycolytic inhibitor 2-deoxy-D-glucose (2-DG) binds to hexokinase in a non-competitive manner and phosphoglucose isomerase in a competitive manner, blocking the initial steps of the glycolytic pathway. Although 2-DG stimulates endoplasmic reticulum (ER) stress, activating the unfolded protein response to restore protein homeostasis, it is unclear which ER stress-related genes are modulated in response to 2-DG treatment in human primary cells. Here, we aimed to determine whether the treatment of monocytes and monocyte-derived macrophages (MDMs) with 2-DG leads to a transcriptional profile specific to ER stress. Methods: We performed bioinformatics analysis to identify differentially expressed genes (DEGs) in previously reported RNA-seq datasets of 2-DG treated cells. RT-qPCR was performed to verify the sequencing data on cultured MDMs. Results: A total of 95 common DEGs were found by transcriptional analysis of monocytes and MDMs treated with 2-DG. Among these, 74 were up-regulated and 21 were down-regulated. Multitranscript analysis showed that DEGs are linked to integrated stress response (GRP78/BiP, PERK, ATF4, CHOP, GADD34, IRE1α, XBP1, SESN2, ASNS, PHGDH), hexosamine biosynthetic pathway (GFAT1, GNA1, PGM3, UAP1), and mannose metabolism (GMPPA and GMPPB). Conclusions: Results reveal that 2-DG triggers a gene expression program that might be involved in restoring protein homeostasis in primary cells. General significance: 2-DG is known to inhibit glycolysis and induce ER stress; however, its effect on gene expression in primary cells is not well understood. This work shows that 2-DG is a stress inducer shifting the metabolic state of monocytes and macrophages

• Autores: Urcuqui Inchima, Silvio; Velilla Hernández, Paula Andrea; Tamayo Molina, Yordi Sebastián; Hernández Sarmiento, Lady Johana
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2023
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/35522
• Acceso en línea: https://hdl.handle.net/10495/35522
• Palabra clave: Desoxiglucosa; Deoxyglucose; Estrés del Retículo Endoplásmico; Endoplasmic Reticulum Stress; Respuesta de Proteína Desplegada; Unfolded Protein Response; Glicosilación; Glycosylation; Células; Cells
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc-nd/2.5/co/