The flavonoid apigenin suppresses vitamin D receptor expression and vitamin D responsiveness in normal human keratinocytes

Apigenin, a flavonoid with chemopreventive properties, induces cellular gro wth arrest, with concomitant inhibition of intracellular signaling cascades and decreased proto-oncogene expression. We report that apigenin potently inhibited vitamin D receptor (VDR) mRNA and protein expression in human ker atinocytes without changes in VDR mRNA half-life. Concurrently, downregulat ion of retinoid X receptor alpha, a dramatic loss of c-myc mRNA, and upregu lation of p21(WAF1) took place. Furthermore, a nearly complete suppression of vitamin D responsiveness was observed as estimated by induction of 24-hy droxylase mRNA. The apigenin effect on VDR expression was shared by some ot her (quercetine and fisetine) but not all tested flavonoids. Interestingly, the apigenin-mediated VDR suppression was counteracted by the NF kappa B i nhibitors sodium salicylate and caffeic acid phenethyl ester. The presented results propose suppression of nuclear receptor levels as a novel mechanis m whereby flavonoids exert their pleiotropic effects. This study may also c ontribute to the understanding of the regulation of VDR expression in epide rmal keratinocytes. (C) 2000 Academic Press.