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Carcinogenesis Advance Access published online on June 10, 2004
Carcinogenesis, doi:10.1093/carcin/bgh205
© 2004 by Oxford University Press
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Received April 5, 2004
Revised May 12, 2004
Accepted May 27, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats

Ken-ichi Fujita 1*, Eiji Matsuda 1, Kazunori Sekine 1, Masaaki Iigo 1, Hiroyuki Tsuda 2

1 Experimental Pathology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Chemotherapy Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2 Experimental Pathology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Chemotherapy Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

* To whom correspondence should be addressed. E-mail: kefujita{at}gan2.res.ncc.go.jp.


  Abstract

Bovine lactoferrin, a multifunctional glycoprotein, has been shown to strongly inhibit development of azoxymethane-induced rat colon tumors. Little, however, is known about the inhibitory mechanisms. We have recently demonstrated that lactoferrin enhances the expression of a member of the tumor necrosis factor receptor family, Fas, in the colon mucosa during both early and late stages of carcinogenesis. Thus, Fas could be involved in bovine lactoferrin-mediated inhibition of tumor development. To investigate this possibility, we studied the influence of bovine lactoferrin on Fas-mediated apoptosis with regard to expression of Fas, activation of caspase-8 and caspase-3, and DNA fragmentation in the colon mucosa of azoxymethane-treated rats. Western blot analysis demonstrated a more than 2.5-fold increase in Fas protein expression, as well as elevation of the active forms of both caspase-8 and caspase-3. Immunohistochemical analysis revealed Fas-positive cells and apoptotic cells preferentially within the proximal colon region, clearly at the site of bovine lactoferrin-mediated tumor inhibition. These results suggest that apoptosis caused by elevated expression of Fas is involved in chemoprevention by lactoferrin of colon carcinogenesis.


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