Protein kinase C isoforms in the chemopreventive effects of a novel vitamin D3 analogue in rat colonic tumorigenesis

Abstract

We recently showed that dietary supplementation with an analogue of 1alpha,25-dihydroxy-vitamin D3, 1alpha,25-dihydroxy-16-ene-23-yne-26,27 F6-vitamin D3 (RO24-5531), reduced the incidence of colonic tumors in rats treated with azoxymethane (AOM). The aim of this study was to determine whether alterations in specific isoforms of protein kinase C (PKC) are involved in this phenomenon. Protein abundance and subcellular distribution of several PKC isoforms were examined and compared in AOM-induced tumors of rats fed control and RO24-5531-supplemented diets. In both AOM-induced colonic adenomas and carcinomas, a significant down-regulation of PKC-alpha, -delta, and -zeta and an up-regulation of PKC-beta11 were found compared with control colonocytes. Dietary RO24-5531 preserved the expression of PKC-zeta and increased the abundance of PKC-epsilon in carcinogen-induced adenomas. Because identical changes in specific isoforms of PKC were found in AOM-induced adenomas and carcinomas, these alterations may be involved in the early stage(s) of colonic malignant transformation. Moreover, the ability of RO24-5531 to block the changes in PKC-zeta induced by AOM, as well as to up-regulate PKC-epsilon, may underlie its ability to prevent adenomas from progressing to carcinomas.