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

G E Koehl1, M Spitzner, J Ousingsawat

  • 1Department of Surgery, University Hospital Regensburg, University of Regensburg, Regensburg, Germany. gudrun.koehl@klinik.uni-regensburg.de

Oncogene
|December 8, 2009
PubMed

Insights

Rapamycin treatment significantly inhibits intestinal neoplasia in mice with adenomatous polyposis coli (APC) gene mutations. This mTOR inhibitor therapy extends lifespan and normalizes ion channel function, offering a novel approach to polyposis treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Familial adenomatous polyposis (FAP) is linked to adenomatous polyposis coli (APC) gene mutations.
  • Mice with APC(Min) mutations develop multiple intestinal neoplasia (Min), mimicking human colorectal cancer progression.
  • Enhanced Akt-mammalian target of rapamycin (mTOR) signaling and oncogenic K(+) channels are observed early in APC(Min/+) colorectal carcinogenesis.

Purpose of the Study:

  • To investigate the therapeutic effect of mTOR inhibition using rapamycin on tumor formation in APC(Min/+) mice.
  • To evaluate the impact of rapamycin on intestinal ion channel regulation in the context of APC mutation-related polyposis.

Main Methods:

  • Long-term continuous administration of rapamycin to APC(Min/+) mice.
  • Assessment of intestinal neoplasia development, survival rates, and body weight.
  • Evaluation of colonic electrolyte transport, epithelial Na(+) channel (ENaC), and oncogenic K(+) ion channels (BK, Elk1, Erg1) at functional and mRNA levels.

Main Results:

  • Rapamycin treatment dramatically inhibited intestinal neoplasia in APC(Min/+) mice.
  • Treated mice showed significantly prolonged survival (39.6+/-3.4 weeks) compared to untreated controls (22.3+/-1.4 weeks), with over 30% surviving past one year.
  • Rapamycin abolished abnormalities in colonic electrolyte transport and suppressed ENaC and oncogenic K(+) channels (BK, Elk1, Erg1) both functionally and at the mRNA level.

Conclusions:

  • Continuous rapamycin prophylaxis markedly inhibits APC mutation-related polyposis development.
  • mTOR inhibition by rapamycin offers a novel therapeutic strategy for colorectal polyposis.
  • Blockade of intestinal oncogenic ion channels represents a potential mechanism of action for rapamycin in this model.

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