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

Abstract

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.