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

Oncogene. 2010 Mar 11;29(10):1553-60. doi: 10.1038/onc.2009.435. Epub 2009 Dec 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics*
  • Animals
  • Codon, Nonsense*
  • Immunosuppressive Agents / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / prevention & control*
  • Intestinal Polyps / genetics
  • Intestinal Polyps / metabolism
  • Intestinal Polyps / prevention & control
  • Intestines / drug effects
  • Intestines / pathology
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ion Channels / metabolism*
  • Mice
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases
  • Weight Loss / drug effects

Substances

  • Adenomatous Polyposis Coli Protein
  • Codon, Nonsense
  • Immunosuppressive Agents
  • Intracellular Signaling Peptides and Proteins
  • Ion Channels
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Sirolimus