Carcinogenesis Advance Access originally published online on June 10, 2004
Carcinogenesis 2004 25(10):1961-1966; doi:10.1093/carcin/bgh205
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis vol.25 no.10 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats
1 Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and 2 Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
3 To whom correspondence should be addressed Email: htsuda{at}med.nagoya-cu.ac.jp
Bovine lactoferrin, a multifunctional glycoprotein, has been shown to strongly inhibit development of azoxymethane (AOM)-induced rat colon tumors. Little, however, is known about the inhibitory mechanisms. We have demonstrated recently 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 AOM-treated rats. Western blot analysis demonstrated a >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.