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Spaan, Claudia N; de Boer, Ruben J; Smit, Wouter L; van der Meer, Jonathan HM; van Roest, Manon; Vermeulen, Jacqueline LM; Koelink, Pim J; Becker, Marte AJ; Go, Simei; Silva, Joana; Faller, William J; van den Brink, Gijs R; Muncan, Vanesa; Heijmans, Jarom

Grp78 is required for intestinal Kras-dependent glycolysis proliferation and adenomagenesis

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  • Medientyp: E-Artikel
  • Titel: Grp78 is required for intestinal Kras-dependent glycolysis proliferation and adenomagenesis
  • Beteiligte: Spaan, Claudia N; de Boer, Ruben J; Smit, Wouter L; van der Meer, Jonathan HM; van Roest, Manon; Vermeulen, Jacqueline LM; Koelink, Pim J; Becker, Marte AJ; Go, Simei; Silva, Joana; Faller, William J; van den Brink, Gijs R; Muncan, Vanesa; Heijmans, Jarom
  • Erschienen: Life Science Alliance, LLC, 2023
  • Erschienen in: Life Science Alliance
  • Sprache: Englisch
  • DOI: 10.26508/lsa.202301912
  • ISSN: 2575-1077
  • Schlagwörter: Health, Toxicology and Mutagenesis ; Plant Science ; Biochemistry, Genetics and Molecular Biology (miscellaneous) ; Ecology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>In development of colorectal cancer, mutations in<jats:italic>APC</jats:italic>are often followed by mutations in oncogene<jats:italic>KRAS</jats:italic>. The latter changes cellular metabolism and is associated with the Warburg phenomenon. Glucose-regulated protein 78 (<jats:italic>Grp78</jats:italic>) is an important regulator of the protein-folding machinery, involved in processing and localization of transmembrane proteins. We hypothesize that targeting<jats:italic>Grp78</jats:italic>in<jats:italic>Apc</jats:italic>and<jats:italic>Kras</jats:italic>(<jats:italic>AK</jats:italic>)-mutant intestines interferes with the metabolic phenotype imposed by<jats:italic>Kras</jats:italic>mutations. In mice with intestinal epithelial mutations in<jats:italic>Apc</jats:italic>,<jats:italic>Kras</jats:italic><jats:sup><jats:italic>G12D</jats:italic></jats:sup>and heterozygosity for<jats:italic>Grp78</jats:italic>(<jats:italic>AK-Grp78</jats:italic><jats:sup><jats:italic>HET</jats:italic></jats:sup>) adenoma number and size is decreased compared with<jats:italic>AK-Grp78</jats:italic><jats:sup><jats:italic>WT</jats:italic></jats:sup>mice. Organoids from<jats:italic>AK-Grp78</jats:italic><jats:sup><jats:italic>WT</jats:italic></jats:sup>mice exhibited a glycolysis metabolism which was completely rescued by<jats:italic>Grp78</jats:italic>heterozygosity. Expression and correct localization of glucose transporter GLUT1 was diminished in<jats:italic>AK-Grp78</jats:italic><jats:sup><jats:italic>HET</jats:italic></jats:sup>cells. GLUT1 inhibition restrained the increased growth observed in<jats:italic>AK</jats:italic>-mutant organoids, whereas<jats:italic>AK-Grp78</jats:italic><jats:sup><jats:italic>HET</jats:italic></jats:sup>organoids were unaffected. We identify<jats:italic>Grp78</jats:italic>as a critical factor in<jats:italic>Kras-</jats:italic>mutated adenomagenesis. This can be attributed to a critical role for<jats:italic>Grp78</jats:italic>in GLUT1 expression and localization, targeting glycolysis and the Warburg effect.</jats:p>
  • Zugangsstatus: Freier Zugang