Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling

Mol Cancer Ther. 2006 Aug;5(8):2060-9. doi: 10.1158/1535-7163.MCT-06-0054.


Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Azoxymethane / adverse effects
  • Cadherins / drug effects
  • Cadherins / metabolism
  • Cell Proliferation / drug effects
  • Colon / drug effects
  • Colon / metabolism
  • Colon / pathology*
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / prevention & control*
  • Cyclin D1 / drug effects
  • Cyclin D1 / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Humans
  • Male
  • Polyethylene Glycols / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Signal Transduction
  • Snail Family Transcription Factors
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • beta Catenin / drug effects
  • beta Catenin / metabolism*


  • Anticarcinogenic Agents
  • Cadherins
  • Snai2 protein, rat
  • Snail Family Transcription Factors
  • Transcription Factors
  • beta Catenin
  • Cyclin D1
  • Polyethylene Glycols
  • Azoxymethane