Chemoprevention of prostate cancer by cholecalciferol (vitamin D3): 25-hydroxylase (CYP27A1) in human prostate epithelial cells.
The 20-30 year latency period for prostate cancer provides an important opportunity to prevent the development of invasive cancer. A logical approach for chemoprevention to reduce incidence is to identify agents, such as, vitamin D, which can inhibit cell proliferation and induce differentiation, are safe, and readily available to the public at low cost. Epidemiological evidence suggests that vitamin D deficiency is associated with increased risk for prostate cancer. We examined the ability and mechanisms of action of cholecalciferol (vitamin D(3)), a precursor of the most biologically active hormone calcitriol, to block or reverse premalignant changes. The immortalized, non-tumorigenic, RWPE-1 human prostate epithelial cell line, was used. Results show that cholecalciferol, at physiological levels: (i) inhibits anchorage-dependent growth (ii) induces differentiation by increasing PSA expression and (iii) exerts its effects by up-regulating vitamin D receptor (VDR), retinoid-X receptors (RXRs), and androgen receptor (AR). Furthermore, we discovered that human prostate epithelial cells constitutively express appreciable levels of 25-hydroxylase CYP27A1 protein, the enzyme which catalyzes the conversion of cholecalciferol to 25(OH)D(3), and that CYP27A1 is up-regulated by cholecalciferol. Recent studies show that human mitochondrial CYP27A1 can also catalyze 1alpha-hydroxylation of 25(OH)D(3) to calcitriol. The presence of 25-hydroxylase in human prostate epithelial cells has not previously been shown. Since human prostate epithelial cells have the necessary enzymes and the rare ability to locally convert cholecalciferol to the active hormone calcitriol, we propose that they are a prime target for chemoprevention of prostate cancer with cholecalciferol whose safety is well established as a supplement in vitamins and fortified foods.
Tokar
Erik J
EJ
Department of Zoology, Michigan State University, S-124 Plant Biology Building, East Lansing, Michigan 48824-1312, USA.
Webber
Mukta M
MM
D002117:Calcitriol / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D002762:Cholecalciferol / Q000494:pharmacology* / Q000627:therapeutic use; D053493:Cholestanetriol 26-Monooxygenase; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000096:biosynthesis / Q000187:drug effects; D047488:Retinoid X Receptors / Q000096:biosynthesis / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism*
D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D017430:Prostate-Specific Antigen; D002117:Calcitriol