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Research Articles: Therapeutics

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

¹ Department of Internal Medicine, Evanston-Northwestern Healthcare; ² Biomedical Engineering Department, Northwestern University, Evanston, Illinois; and Departments of ³ Pathology and ⁴ Internal Medicine, University of Chicago Medical Center, Chicago, Illinois

Requests for reprints: Ramesh K. Wali, Feinberg School of Medicine, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, IL 60201. Phone: 847-570-4108; Fax: 847-733-5451. E-mail: rwali{at}enh.org

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–ß-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 ß-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 ß-catenin transcriptional activity. PEG did not alter total ß-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of ß-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. [Mol Cancer Ther 2006;5(8):2060–9]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: This article was presented in part in abstract form at Digestive Disease Week Meetings.

Received 1/30/06; revised 5/ 9/06; accepted 5/31/06.