Grp78 is required for intestinal Kras-dependent glycolysis proliferation and adenomagenesis
Claudia N Spaan, Ruben J de Boer, Wouter L Smit, Jonathan HM van der Meer, Manon van Roest, Jacqueline LM Vermeulen, Pim J Koelink, Marte AJ Becker, Simei Go, Joana Silva, William J Faller, Gijs R van den Brink, Vanesa Muncan, Jarom Heijmans- Health, Toxicology and Mutagenesis
- Plant Science
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Ecology
In development of colorectal cancer, mutations inAPCare often followed by mutations in oncogeneKRAS. The latter changes cellular metabolism and is associated with the Warburg phenomenon. Glucose-regulated protein 78 (Grp78) is an important regulator of the protein-folding machinery, involved in processing and localization of transmembrane proteins. We hypothesize that targetingGrp78inApcandKras(AK)-mutant intestines interferes with the metabolic phenotype imposed byKrasmutations. In mice with intestinal epithelial mutations inApc,KrasG12Dand heterozygosity forGrp78(AK-Grp78HET) adenoma number and size is decreased compared withAK-Grp78WTmice. Organoids fromAK-Grp78WTmice exhibited a glycolysis metabolism which was completely rescued byGrp78heterozygosity. Expression and correct localization of glucose transporter GLUT1 was diminished inAK-Grp78HETcells. GLUT1 inhibition restrained the increased growth observed inAK-mutant organoids, whereasAK-Grp78HETorganoids were unaffected. We identifyGrp78as a critical factor inKras-mutated adenomagenesis. This can be attributed to a critical role forGrp78in GLUT1 expression and localization, targeting glycolysis and the Warburg effect.