APC Sensitive Gastric Acid Secretion

Abstract

Adenomatous polyposis coli (APC) is a tumor suppressor gene inactivated in familial adenomatous polyposis and sporadic colorectal cancer. Mice carrying a loss-of-function mutation in the apc gene (apc^Min/+) spontaneously develop gastrointestinal tumors. APC fosters degradation of β-catenin, which in turn upregulates the serum- and glucocorticoid-inducible kinase SGK1. SGK1 stimulates KCNQ1, which is required for luminal K⁺ recycling and thus for gastric acid secretion. BCECF-fluorescence was utilized to determine gastric acid secretion in isolated gastric glands from apc^Min/+ mice and their wild type littermates (apc^+/+). Western blotting was employed to analyse β-catenin and SGK1 expression and immunohistochemistry to determine KCNQ1 protein abundance. β-catenin and SGK1 expression were enhanced in apc^Min/+ mice. Cytosolic pH was similar in apc^Min/+ mice and apc^+/+ mice. Na⁺-independent pH recovery following an ammonium pulse (ΔpH/min), which reflects H⁺/K⁺ ATPase activity, was, however, significantly faster in apc^Min/+ mice than in apc^+/+mice. In both genotypes ΔpH/min was abolished in the presence of H⁺/K⁺ ATPase inhibitor omeprazole (100 μM). Treatment of apc^Min/+ and apc^+/+mice with 5 μM forskolin 15 minutes prior to the experiment or increase in local K⁺-concentrations to 35 mM (replacing Na⁺/NMDG) significantly increased ΔpH/min and abrogated the differences between genotypes. The increase of ΔpH/min in apc^Min/+mice required SGK1, as it was abolished by additional knockout of SGK1 (apc^Min/+/sgk1^-/-). In conclusion, basal gastric acid secretion is significantly enhanced in apc^Min/+mice, pointing to a role of APC in the regulation of gastric acid secretion. The effect of APC requires H⁺/K⁺ ATPase activity and is at least partially due to SGK1-dependent upregulation of KCNQ1.