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 GSK3β, which phosphorylates β-catenin thus fostering its degradation. β-catenin upregulates the serum-and glucocorticoid-inducible kinase Sgk1, which inhibits GSK3β. 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. β-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 β-catenin protein abundance was significantly higher in sgk1 +/+ mice than in sgk1 -/- mice. β-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 β-catenin protein abundance. Copyright © 2010 S. Karger AG, Basel.