SGK1-dependent Intestinal Tumor Growth in APC-deficient Mice

Abstract

Adenomatous polyposis coli (APC) is inactivated in familial adenomatous polyposis and sporadic colorectal cancer. Mice carrying defective APC (apc(Min/+)) spontaneously develop gastrointestinal tumors. APC binds GSK3beta, which phosphorylates beta-catenin thus fostering its degradation. beta-catenin upregulates the serum- and glucocorticoid-inducible kinase Sgk1, which inhibits GSK3beta. The present study explored the role of SGK1 in tumor growth of apc(Min/+)mice. apc(Min/+)mice were crossed with SGK1-knockout mice (sgk1(-/-)) and their wild type littermates (sgk1(+/+)) generating apc(Min/+)/sgk1(-/-)mice and apc(Min/+)/sgk1(+/+)mice. beta-catenin abundance was determined by Western blotting and confocal microscopy. As a result apc(Min/+)/sgk1(+/+)mice developed significantly more intestinal tumors than apc(Min/+)/sgk1(-/-)mice. Following chemical cancerogenesis, colonic beta-catenin protein abundance was significantly higher in sgk1(+/+)mice than in sgk1(-/-)mice. beta-catenin expression was significantly increased in HEK293 cells treated with dexamethasone for upregulation of Sgk1. In conclusion, SGK1 expression favors the development of intestinal tumors in APC-deficient mice, an effect at least partially due to enhanced beta-catenin protein abundance.