Vitamin D metabolism in human prostate cells: implications for prostate cancer chemoprevention by vitamin D.

BACKGROUND Prostate cells can produce 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) from 25-hydroxyvitamin D3 (25(OH)D3) to regulate their own growth. Here, the questions of whether prostate cells express vitamin D-25-hydroxylase (25-OHase) and can convert vitamin D3 to 1alpha,25(OH)2D3 were investigated. MATERIALS AND METHODS Protein and receptor binding assays were used to determine 25(OH)D3 and 1alpha,25(OH)2D3, respectively. Measurements of proliferation by 3H-thymidine incorporation, and 1alpha,25(OH)2D-responsive gene expression by real-time qPCR and by Western blot were used as functional assays for the presence of 25-OHase activity. RESULTS Prostate cells metabolized vitamin D3 to 1alpha,25(OH)2D3. Vitamin D3 up-regulated 25(OH)D-24R-hydroxylase and IGFBP3, two 1alpha,25(OH)2D-responsive genes, in prostate cells. CYP2R1 was the major form of 25-OHase expressed in normal and cancerous prostate cells as determined by qPCR. CONCLUSION The autocrine synthesis of 1alpha,25(OH)2D3 from vitamin D3 suggests that maintaining adequate levels of serum vitamin D could be a safe and effective chemo-preventive measure to decrease the risk of prostate cancer.

[1]  Y. Ohyama,et al.  Eight cytochrome P450s catalyze vitamin D metabolism. , 2004, Frontiers in bioscience : a journal and virtual library.

[2]  Jeffrey B. Cheng,et al.  Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B. Hollis,et al.  CYP3A4 is a Human Microsomal Vitamin D 25‐Hydroxylase , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  M. Holick,et al.  Vitamin D and prostate cancer prevention and treatment , 2003, Trends in Endocrinology & Metabolism.

[5]  Jeffrey B. Cheng,et al.  De-orphanization of Cytochrome P450 2R1 , 2003, Journal of Biological Chemistry.

[6]  M. Meurer,et al.  Extrarenal sites of calcitriol synthesis: the particular role of the skin. , 2003, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[7]  M. Holick,et al.  Real–Time Quantitative Reverse Transcriptase-Polymerase Chain Reaction (RT–PCR) Analysis of the Vitamin D Pathway in UV Irradiated Keratinocytes , 2002 .

[8]  P. Cohen,et al.  Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1. , 2001, The Journal of urology.

[9]  D. Feldman,et al.  The role of vitamin D in prostate cancer , 2001, Steroids.

[10]  I. Schuster,et al.  Skin is an autonomous organ in synthesis, two-step activation and degradation of vitamin D3: CYP27 in epidermis completes the set of essential vitamin D3-hydroxylases , 2001, Steroids.

[11]  K. Burnstein,et al.  The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  R. Vieth,et al.  Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. , 1999, The American journal of clinical nutrition.

[13]  H. DeLuca,et al.  Current understanding of the molecular actions of vitamin D. , 1998, Physiological reviews.

[14]  M. Gascon-Barré.  CHAPTER 4 – The Vitamin D 25-Hydroxylase , 1997 .

[15]  G. Miller,et al.  Stable expression of the nuclear vitamin D receptor in the human prostatic carcinoma cell line JCA-1: evidence that the antiproliferative effects of 1 alpha, 25-dihydroxyvitamin D3 are mediated exclusively through the genomic signaling pathway. , 1996, Endocrinology.

[16]  M. Holick,et al.  The antiproliferative and differentiative activities of 1,25-dihydroxyvitamin D3 are potentiated by epidermal growth factor and attenuated by insulin in cultured human keratinocytes. , 1995, The Journal of investigative dermatology.

[17]  D. Peehl,et al.  Actions of vitamin D3, analogs on human prostate cancer cell lines: comparison with 1,25-dihydroxyvitamin D3. , 1995, Endocrinology.

[18]  T. Chen,et al.  A method for the determination of the circulating concentration of 1,25-dihydroxyvitamin D. , 1990, The Journal of nutritional biochemistry.