Koehl, G. E. and Spitzner, M. and Ousingsawat, J. and Schreiber, R. and Geissler, E. K. and Kunzelmann, K. (2010) Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APC(Min/+) mice. ONCOGENE, 29 (10). pp. 1553-1560. ISSN 0950-9232,
Full text not available from this repository. (Request a copy)Abstract
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. Oncogene (2010) 29, 1553-1560; doi:10.1038/onc.2009.435; published online 7 December 2009
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GATED POTASSIUM CHANNELS; K+ CHANNELS; ADENOMATOUS POLYPOSIS; COLORECTAL-CANCER; COLONIC-CARCINOMA; APC GENE; CELLS; PROLIFERATION; MTOR; COMBINATION; mTOR; familial adenomatous polyposis; ion channels; APCMin/ plus mice; rapamycin; Sirolimus |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Aug 2020 04:42 |
| Last Modified: | 06 Aug 2020 04:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25118 |
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