APC Sensitive Gastric Acid Secretion
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<sup>Min/+</sup>) 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<sup>+</sup> recycling and thus for gastric acid secretion. BCECF-fluorescence was utilized to determine gastric acid secretion in isolated gastric glands from apc<sup>Min/+</sup> mice and their wild type littermates (apc<sup>+/+</sup>). 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<sup>Min/+</sup> mice. Cytosolic pH was similar in apc<sup>Min/+</sup> mice and apc<sup>+/+</sup> mice. Na<sup>+</sup>-independent pH recovery following an ammonium pulse (ΔpH/min), which reflects H<sup>+</sup>/K<sup>+</sup> ATPase activity, was, however, significantly faster in apc<sup>Min/+</sup> mice than in apc<sup>+/+</sup>mice. In both genotypes ΔpH/min was abolished in the presence of H<sup>+</sup>/K<sup>+</sup> ATPase inhibitor omeprazole (100 μM). Treatment of apc<sup>Min/+</sup> and apc<sup>+/+</sup>mice with 5 μM forskolin 15 minutes prior to the experiment or increase in local K<sup>+</sup>-concentrations to 35 mM (replacing Na<sup>+</sup>/NMDG) significantly increased ΔpH/min and abrogated the differences between genotypes. The increase of ΔpH/min in apc<sup>Min/+</sup>mice required SGK1, as it was abolished by additional knockout of SGK1 (apc<sup>Min/+</sup>/sgk1<sup>-/-</sup>). In conclusion, basal gastric acid secretion is significantly enhanced in apc<sup>Min/+</sup>mice, pointing to a role of APC in the regulation of gastric acid secretion. The effect of APC requires H<sup>+</sup>/K<sup>+</sup> ATPase activity and is at least partially due to SGK1-dependent upregulation of KCNQ1.