Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APC super(Min/+) mice

• Published in: Oncogene Vol. 29; no. 10; pp. 1553 - 1560
• Main Authors: Koehl, G E, Spitzner, M, Ousingsawat, J, Schreiber, R, Geissler, E K, Kunzelmann, K
• Format: Journal Article
• Language: English
• Published: 11-03-2010
• ISSN: 0950-9232
• DOI: 10.1038/onc.2009.435

The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis. Mice with a heterozygous APC super(Min) mutation develop multiple intestinal neoplasia (Min) leading to premature death. Early in colorectal carcinogenesis, APC super(Min/+) mice show enhanced Akt-mammalian target of rapamycin (mTOR) signaling, which is paralleled by upregulation of oncogenic K super(+) channels. In this study, we tested the effect of mTOR inhibition with rapamycin on tumor formation in APC super(Min/+) mice and evaluated ion channel regulation. We found that continuous long-term rapamycin treatment of APC super(Min/+) mice dramatically inhibits intestinal neoplasia. Moreover, although untreated APC super(Min/+) mice lose weight, experience intestinal bleeding and succumb to multiple neoplasia by 22.3c1.4 weeks of age, mice treated with rapamycin maintain stable weight and survive long term (39.6c3.4 weeks), with more than 30% surviving >1 year. Impressively, abnormalities in colonic electrolyte transport typical for APC super(Min/+) mice are abolished, along with the suppression of epithelial Na super(+) channel (ENaC) and oncogenic K super(+) 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.