Upregulation of colonic ion channels in APC ( Min/+ ) mice.
The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in almost all human colonic cancers. Disturbances in Na(+) absorption have been observed in colonic cancer, and ion channels such as ether a go-go (Eag) or Ca(2+)-sensitive BK channels have been recognized for their oncogenic potential. APC ( Min/+ ) mice have reduced APC expression and develop multiple intestinal neoplasias (Min). Ion channels in the colonic epithelium were examined using electrophysiology and molecular techniques. APC ( Min/+ ) mice developed intestinal neoplasia and experienced a significant weight loss. Due to intestinal bleedings, the hematocrit was largely reduced and plasma aldosterone levels were enhanced. Rectal potential measurements in vivo indicated an increase in amiloride-sensitive Na(+) absorption in APC ( Min/+ ) mice. Quantitative Ussing chamber studies demonstrated enhanced Na(+) absorption via epithelial Na(+) channels (ENaC) and suggested enhanced activity of oncogenic BK and Eag-1 channels. Patch clamp and fluorescence measurements on isolated crypts suggested enhanced K(+) channel activity in the surface epithelium. ENaC-mRNA and membrane protein expression was enhanced in colonic surface epithelial cells. The data suggest that reduced expression of the APC gene with upregulation of the downstream proteins Akt and mTOR and subsequent hyperaldosteronism is paralleled by upregulation of oncogenic potassium channels and enhanced colonic Na(+) absorption.
Ousingsawat
Jiraporn
J
Institut für Physiologie, Universität Regensburg, Universitätsstrasse 31, 93053, Regensburg, Germany.
Spitzner
Melanie
M
Schreiber
Rainer
R
Kunzelmann
Karl
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003106:Colon / Q000033:anatomy & histology / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism; D017491:Genes, APC; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D053503:Epithelial Sodium Channels; D007473:Ion Channels; D015221:Potassium Channels; D012964:Sodium