Carcinogenesis Advance Access originally published online on August 2, 2006
Carcinogenesis 2007 28(2):321-327; doi:10.1093/carcin/bgl127
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Apc mutation induces resistance of colonic cells to lipoperoxide-triggered apoptosis induced by faecal water from haem-fed rats
1 Ecole Nationale Vétérinaire Toulouse, UMR INRA-ENVT Xénobiotiques 23 chemin des Capelles, 31076 Toulouse, France
2 Institut National de la Recherche Agronomique, UMR INRA-ENVT Xénobiotiques 180 chemin de Tournefeuille, 31931 Toulouse, France
3 Inserm E 0211, Nutrition Croissance et Cancer 10 Boulevard Tonnellé, 37032 Tours Cedex, France
*To whom correspondence should be addressed. Email: f.pierre{at}envt.fr
Recent epidemiological studies suggest that high meat intake is associated with promotion of colon cancer linked with haem-iron intake. We previously reported that dietary haem, in the form of either haemoglobin or meat, promotes precancerous lesions in the colon of rats given a low-calcium diet. The mechanism of promotion by haem is not known, but is associated with increased lipid peroxidation in faecal water and strong cytotoxic activity of faecal water on a cancerous mouse colonic epithelial cell line. To better understand the involvement of faecal water components of haem-fed rats in colon-cancer promotion, we explored the effect of faecal water on normal [adenomatous polyposis coli (Apc) +/+] or premalignant cells (Apc –/+). Further, we tested if this effect was correlated to lipoperoxidation and 4-hydroxynonenal (HNE). We show here for the first time that heterozygote Apc mutation represents a strong selective advantage, via resistance to apoptosis induction (caspase 3 pathway), for colonic cells exposed to a haem-iron-induced lipoperoxidation. The fact that HNE treatment of the cells provoked the same effects as the faecal water of rats fed the haem-rich diet suggests that this compound triggers apoptosis in those cells. We propose that this mechanism could be involved in the promotion of colon carcinogenesis by haem in vivo.
Abbreviations: Apc, adenomatous polyposis coli; CD, control diet; DMEM, Dulbecco-modified essential medium; HNE, 4-hydroxynonenal; PBS, phosphate-buffered saline; SD, standard deviation; TBARs, thiobarbituric acid reactive substances
Received August 8, 2005; revised June 13, 2006; accepted June 13, 2006.