Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice

Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13544-9. doi: 10.1073/pnas.0800041105. Epub 2008 Sep 3.


The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status in gastrointestinal tumors has not been characterized thoroughly. We have found that the mTORC1 pathway is activated with increased expression of the mTOR protein in intestinal polyps of the Apc(Delta716) heterozygous mutant mouse, a model for human familial adenomatous polyposis. An 8-week treatment with RAD001 (everolimus) suppressed the mTORC1 activity in these polyps and inhibited proliferation of the adenoma cells as well as tumor angiogenesis, which significantly reduced not only the number of polyps but also their size. beta-Catenin knockdown in the colon cancer cell lines reduced the mTOR level and thereby inhibited the mTORC1 signaling. These results suggest that the Wnt signaling contributes to mTORC1 activation through the increased level of mTOR and that the activation plays important roles in the intestinal polyp formation and growth. Indeed, long-term RAD001 treatment significantly reduced mortality of the Apc(Delta716) mice. Thus, we propose that the mTOR inhibitors may be efficacious for therapy and prevention of colonic adenomas and cancers with Wnt signaling activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / blood supply
  • Adenoma / drug therapy
  • Adenoma / pathology
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism*
  • Animals
  • Cell Proliferation / drug effects
  • Everolimus
  • Female
  • Intestinal Polyps / metabolism*
  • Intestinal Polyps / pathology
  • Intestinal Polyps / prevention & control*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes
  • Proteins
  • Signal Transduction* / drug effects
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • Survival Rate
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism*
  • Wnt Proteins / metabolism


  • Adenomatous Polyposis Coli Protein
  • Multiprotein Complexes
  • Proteins
  • Transcription Factors
  • Wnt Proteins
  • Everolimus
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Sirolimus