| First Author | Spaan CN | Year | 2023 |
| Journal | Life Sci Alliance | Volume | 6 |
| Issue | 11 | PubMed ID | 37643866 |
| Mgi Jnum | J:340295 | Mgi Id | MGI:7527811 |
| Doi | 10.26508/lsa.202301912 | Citation | Spaan CN, et al. (2023) Grp78 is required for intestinal Kras-dependent glycolysis proliferation and adenomagenesis. Life Sci Alliance 6(11) |
| abstractText | In development of colorectal cancer, mutations in APC are often followed by mutations in oncogene KRAS 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 targeting Grp78 in Apc and Kras (AK)-mutant intestines interferes with the metabolic phenotype imposed by Kras mutations. In mice with intestinal epithelial mutations in Apc, Kras (G12D) and heterozygosity for Grp78 (AK-Grp78 (HET) ) adenoma number and size is decreased compared with AK-Grp78 (WT) mice. Organoids from AK-Grp78 (WT) mice exhibited a glycolysis metabolism which was completely rescued by Grp78 heterozygosity. Expression and correct localization of glucose transporter GLUT1 was diminished in AK-Grp78 (HET) cells. GLUT1 inhibition restrained the increased growth observed in AK-mutant organoids, whereas AK-Grp78 (HET) organoids were unaffected. We identify Grp78 as a critical factor in Kras-mutated adenomagenesis. This can be attributed to a critical role for Grp78 in GLUT1 expression and localization, targeting glycolysis and the Warburg effect. |
