Genistein inhibits vitamin D hydroxylases CYP24 and CYP27B1 expression in prostate cells.
In human prostate cancer cells, the availability of the steroid hormone 1,25-dihydroxyvitamin D(3) for antimitotic action is determined through the activity of the two enzymes CYP24 and CYP27B1, viz. 25-hydroxyvitamin D-24-hydroxylase and 25-hydroxyvitamin D-1alpha-hydroxylase. High performance liquid chromatography (HPLC) analysis of [(3)H]25(OH)D(3) metabolism in human prostate cancer DU-145 cells revealed that genistein and other isoflavonoids, such as dihydrogenistein and daidzein, as well as the antiestrogenic compound ICI 182,780, inhibited Vitamin D-metabolizing enzyme activities. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that only in case of genistein this was due to transcriptional inhibition of CYP24 and CYP27B1 gene expressions. In case of CYP27B1, reduction of gene activity involves histone deacetylation because genistein was inactive in the presence of the histone deactylase inhibitor trichostatin A. In contrast, under the same condition, CYP24 gene activity was largely suppressed. In summary, our results suggest that a combined effect of genistein and trichostatin A could increase the responsiveness of human prostate cancer cells to the antiproliferative action of 1,25-dihydroxyvitamin D(3).
Department of Pathophysiology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Hesso
H
Farhan
Kristiina
K
Wähälä
Heide S
HS
Cross
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D000077267:Fulvestrant; D019833:Genistein / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D048789:Phytoestrogens; D028321:Plant Preparations; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004968:Estrogens, Non-Steroidal; D006877:Hydroxamic Acids; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D012333:RNA, Messenger; C464747:dihydrogenistin; D014807:Vitamin D; D000077267:Fulvestrant; C012589:trichostatin A; D004958:Estradiol; C004742:daidzein; D019833:Genistein; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D006655:Histone Deacetylases