sirolimus and Intestinal-Polyps

Topics: Adenomatous Polyposis Coli; Adolescent; Antibiotics, Antineoplastic; Colonic Polyps; Colonoscopy; Duodenal Neoplasms; Endoscopy, Digestive System; Humans; Intestinal Polyps; Male; Sirolimus; Treatment Outcome

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.

Topics: Adenomatous Polyposis Coli Protein; Animals; Codon, Nonsense; Immunosuppressive Agents; Intestinal Mucosa; Intestinal Neoplasms; Intestinal Polyps; Intestines; Intracellular Signaling Peptides and Proteins; Ion Channels; Mice; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Weight Loss

Germline mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder with a predisposition to gastrointestinal polyposis and cancer. Hyperactivation of mTOR-signaling has been associated with PJS. We previously reported that rapamycin treatment of Lkb1(+/-) mice after the onset of polyposis reduced the polyp burden. Here we evaluated the preventive efficacy of rapamycin on Peutz-Jeghers polyposis. We found that rapamycin treatment of Lkb1(+/-) mice initiated before the onset of polyposis in Lkb1(+/-) mice led to a dramatic reduction in both polyp burden and polyp size and this reduction was associated with decreased phosphorylation levels of S6 and 4EBP1. Together, these findings support the use of rapamycin as an option for chemoprevention and treatment of PJS.

Topics: AMP-Activated Protein Kinases; Animals; Antibiotics, Antineoplastic; Carrier Proteins; Disease Models, Animal; Germ-Line Mutation; Intestinal Polyps; Mice; Mice, Knockout; Peutz-Jeghers Syndrome; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Serine-Threonine Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Cell Proliferation; Everolimus; Female; Intestinal Polyps; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Transgenic; Multiprotein Complexes; Proteins; Signal Transduction; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases; Transcription Factors; Wnt Proteins