Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APC(Min/+) mice.
The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis. Mice with a heterozygous APC(Min) mutation develop multiple intestinal neoplasia (Min) leading to premature death. Early in colorectal carcinogenesis, APC(Min/+) mice show enhanced Akt-mammalian target of rapamycin (mTOR) signaling, which is paralleled by upregulation of oncogenic K(+) channels. In this study, we tested the effect of mTOR inhibition with rapamycin on tumor formation in APC(Min/+) mice and evaluated ion channel regulation. We found that continuous long-term rapamycin treatment of APC(Min/+) mice dramatically inhibits intestinal neoplasia. Moreover, although untreated APC(Min/+) mice lose weight, experience intestinal bleeding and succumb to multiple neoplasia by 22.3+/-1.4 weeks of age, mice treated with rapamycin maintain stable weight and survive long term (39.6+/-3.4 weeks), with more than 30% surviving >1 year. Impressively, abnormalities in colonic electrolyte transport typical for APC(Min/+) mice are abolished, along with the suppression of epithelial Na(+) channel (ENaC) and oncogenic K(+) ion channels BK, Elk1 and Erg1, both functionally and at mRNA levels. These results show that continuous prophylaxis by rapamycin markedly inhibits the development of APC mutation-related polyposis, and suggest a novel contributing mechanism of action through the blockade of intestinal oncogenic ion channels.
Koehl
G E
GE
Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany. gudrun.koehl@klinik.uni-regensburg.de
Spitzner
M
M
Ousingsawat
J
J
Schreiber
R
R
Geissler
E K
EK
Kunzelmann
K
K
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D018389:Codon, Nonsense; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D015431:Weight Loss / Q000187:drug effects
D025601:Adenomatous Polyposis Coli Protein; D018389:Codon, Nonsense; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus