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 (apcMin/+) 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 apcMin/+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 apcMin/+mice. Cytosolic pH was similar in apcMin/+ 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 apcMin/+ 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 apcMin/+ 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 apcMin/+mice required SGK1, as it was abolished by additional knockout of SGK1 (apcMin/+/sgk1-/-). In conclusion, basal gastric acid secretion is significantly enhanced in apcMin/+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.
A. Rotte, Bhandaru, M., Föller, M., Dr. Raja Biswas, Mack, A. F., Friedrich, B., Rexhepaj, R., Nasir, O., Ackermann, T. F., Boini, K. M., and , “APC sensitive gastric acid secretion”, Cellular Physiology and Biochemistry, vol. 23, pp. 133–142, 2009.