Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats.
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.
Fujita
Ken-ichi
K
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Matsuda
Eiji
E
Sekine
Kazunori
K
Iigo
Masaaki
M
Tsuda
Hiroyuki
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000662:veterinary; D004789:Enzyme Activation / Q000187:drug effects; D007124:Immunoenzyme Techniques; D007781:Lactoferrin / Q000627:therapeutic use*; D008297:Male; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor
D002273:Carcinogens; C491898:Fas protein, rat; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D007781:Lactoferrin; D020169:Caspases; D001397:Azoxymethane