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

Background and Aims: We recently showed that dietary supplementation with an analogue of 1α,25-dihydroxy-vitamin D₃, 1α,25-dihydroxy-16-ene- 23-yne-26,27 F₆-vitamin D₃ (R024-5531), 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. Methods: 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. Results: In both AOM-induced colonic adenomas and carcinomas, a significant down- regulation of PKC-α, -δ, and -ζ and an up-regulation of PKC-β(II) were found compared with control colonocytes. Dietary R024-5531 preserved the expression of PKC-ζ and increased the abundance of PKC-ε in carcinogen- induced adenomas. Conclusions: 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 R024-5531 to block the changes in PKC-ζ induced by AOM, as well as to up-regulate PKC-ε, may underlie its ability to prevent adenomas from progressing to carcinomas.