24-25-dihydroxyvitamin-d-3 and Prostatic-Neoplasms

Vitamin D deficiency increases risk of prostate cancer. According to our recent results, the key Vitamin D hormone involved in the regulation of cell proliferation in prostate is 25(OH) Vitamin D3. It is mainly acting directly through the Vitamin D receptor (VDR), but partially also through its 1alpha-hydroxylation in the prostate. A deficiency of 25(OH) Vitamin D is common especially during the winter season in the Northern and Southern latitudes due to an insufficient sun exposure, but Vitamin D deficient diet may partially contribute to it. A lack of Vitamin D action may also be due to an altered metabolism or Vitamin D resistance. Vitamin D resistance might be brought up by several mechanisms: Firstly, an increased 24-hydroxylation may increase the inactivation of hormonal Vitamin D metabolites resulting in a Vitamin D resistance. This is obvious in the cancers in which an oncogenic amplification of 24-hydroxykase gene takes place, although an amplification of this gene in prostate cancer has not yet been described. During the aging, the activity of 24-hydroxylase increases, whereas 1alpha-hydroxylation decreases. Furthermore, it is possible that a high serum concentration of 25(OH)D3 could induce 24-hydroxylase expression in prostate. Secondly, Vitamin D receptor gene polymorphism or defects may result in a partial or complete Vitamin D resistance. Thirdly, an overexpression or hyperphosphorylation of retinoblastoma protein may result in an inefficient mitotic control by Vitamin D. Fourthly, endogenous steroids (reviewed by [D.M. Peehl, D. Feldman, Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer, J. Steroid Biochem. Mol. Biol. (2004)]) and phytoestrogens may modulate the expression of Vitamin D metabolizing enzymes. In summary, the local metabolism of hormonal Vitamin D seems to play an important role in the development and progression of prostate cancer.

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Calcifediol; Calcitriol; Cell Proliferation; Cholecalciferol; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Gene Expression Regulation, Neoplastic; Humans; Male; Phytoestrogens; Prostate; Prostatic Neoplasms; Receptors, Calcitriol; Steroid Hydroxylases; Vitamin D3 24-Hydroxylase

In addition to its role in calcium and phosphorus metabolism, calcitriol (1,25-dihydroxyvitamin D3; 1,25-D3) demonstrates multiple effects on cell proliferation/differentiation by expressing major histocompatibility complex (MHC) antigens and intercellular adhesion molecule-1 (ICAM-1). It has recently been reported that 1,25-D3 inhibits the growth of prostatic cancer (PCa) cells. In this study we examined the effect of 1,25-D3 on both the growth and expression of HLA-ABC, HLA-DR and ICAM-1 antigens in PCa cells.. Four human PCa cell lines (PC-3, PPC-1, ALVA-41 and ALVA-101) were examined. The cell numbers were enumerated, and the effects of interferon-y (IFN-gamma) and 1,25-D3 on the expression of HLA-ABC, HLA-DR and ICAM-1 were quantitated by flow cytometry.. A dose-dependent antiproliferative effect of 1,25-D3 was found in all PCa cells lines except ALVA-41.1,25-D3 was approximately 10 times as potent as its analogue 24,25-dihydroxyvitamin D3 in inhibiting the growth of PC-3 cells. Also, the relative inhibitory ability of these compounds paralleled the strength of their binding affinities for the 1,25-D3 receptor, indicating that the antiproliferative effect may require a receptor-ligand interaction. HLA-ABC was expressed in PC-3, ALVA-41 and ALVA-101, but not in PPC-1 cells, while HLA-DR was not expressed on any of the tested cells. IFN-gammacould enhance or induce HLA-ABC but not HLA-DR expression in the tested cells. ICAM-1 was expressed in all cells and slightly upregulated by IFN-gamma.. In this study 1,25-D3 had an antiproliferative effect on 3 of the 4 examined PCa cell lines.

Topics: 24,25-Dihydroxyvitamin D 3; Calcitriol; Cell Division; Dose-Response Relationship, Drug; HLA Antigens; HLA-DR Antigens; Humans; Intercellular Adhesion Molecule-1; Interferon-gamma; Male; Prostatic Neoplasms; Tumor Cells, Cultured

Although prostatic cancer is often viewed as an androgen-dependent malignancy, a number of other hormones including 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] are now recognized to modulate its growth and differentiated phenotype. Seven different continuous human prostatic carcinoma cell lines were examined for the presence of biologically active receptors for 1alpha,25(OH)2D3. All seven lines were found to contain mRNA for the vitamin D receptor using an RNase protection assay. Six of the seven cell lines were found to have high-affinity saturable binding sites for 1alpha,25(OH)2D3. The seventh line was found to contain vitamin D receptors by sucrose gradient analysis. All seven lines were found to express 24-hydroxylase activity by a HPLC assay that measures the conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3. 24-Hydroxylase activity was up-regulated in all seven cell lines by preincubation with 1alpha,25(OH)2D3. In the presence of fetal bovine serum, the growth of four of the seven cell lines was inhibited. In the majority of cell lines growth inhibition was related not only to the number of receptors per cell, but also in inverse proportion to the 24-hydroxylase activity of each cell line. The ubiquitous presence of vitamin D receptor and 24-hydroxylase activity in human prostatic carcinoma cells suggests new alternatives for the pharmacological treatment of advanced prostatic cancer and implies that chemoprevention strategies could also make use of this endocrine axis.

Topics: 24,25-Dihydroxyvitamin D 3; Calcitriol; Cell Division; Cytochrome P-450 Enzyme System; Humans; Male; Prostatic Neoplasms; Receptors, Calcitriol; Steroid Hydroxylases; Tumor Cells, Cultured; Vitamin D3 24-Hydroxylase