Prostatic 25‐hydroxyvitamin D‐1α‐hydroxylase and its implication in prostate cancer

Chen, Thomas; Wang, Lilin; Whitlatch, Lyman W.; Flanagan, John N.; Holick, Michael F.

doi:10.1002/jcb.10342

Cited by 125 publications

(75 citation statements)

References 23 publications

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“…Interestingly, epithelial prostate cells express 1␣-hydroxylase, which is required for 1,25-dihydroxyvitamin D 3 synthesis (51). The extrarenal synthesis of 1,25-dihydroxyvitamin D 3 in the prostate could have a local growth-regulating physiological role, as suggested by the marked decrease of 1␣-hydroxylase activity in prostate cancer cell lines (52), and possibly also an anti-inflammatory one. Although the prostate has been long recognized as a target organ of VDR agonists (49), its capacity to respond to these agents has thus far been probed only for the treatment of prostate cancer (53) and BPH (20,21).…”

Section: Discussionmentioning

confidence: 99%

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

Penna

Amuchastegui

Cossetti

et al. 2006

The Journal of Immunology

119

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On the basis of on the marked inhibitory activity of the vitamin D receptor agonist Elocalcitol on basal and growth factor-induced proliferation of human prostate cells and on its potent anti-inflammatory properties, we have tested its capacity to treat experimental autoimmune prostatitis (EAP) induced by injection of prostate homogenate-CFA in nonobese diabetic (NOD) mice. Administration of Elocalcitol, at normocalcemic doses, for 2 wk in already established EAP significantly inhibits the intraprostatic cell infiltrate, leading to a profound reduction in the number of CD4+ and CD8+ T cells, B cells, macrophages, dendritic cells, and I-Ag7-positive cells. Immunohistological analysis demonstrates reduced cell proliferation and increased apoptosis of resident and infiltrating cells. Significantly decreased production of the proinflammatory cytokines IFN-γ and IL-17 is observed in prostate-draining lymph node T cells from Elocalcitol-treated NOD mice stimulated by TCR ligation. In addition, Elocalcitol treatment reduces IFN-γ production by prostate-infiltrating CD4+ T cells and draining lymph node T cells specific for an immunodominant peptide naturally processed from prostate steroid-binding protein, a prostate-specific autoantigen. Finally, CD4+ splenic T cells from Elocalcitol-treated NOD mice show decreased ability, upon adoptive transfer into NOD.SCID recipients, to induce autoimmune prostatitis, paralleled by a reduced capacity to produce IFN-γ in response to prostate steroid-binding protein. The results indicate that Elocalcitol is able to interfere with key pathogenic events in already established EAP in the NOD mouse. These data show a novel indication for vitamin D receptor agonists and indicate that treatment with Elocalcitol may inhibit the intraprostatic inflammatory response in chronic prostatitis/chronic pelvic pain syndrome patients.

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Section: Discussionmentioning

confidence: 99%

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

Penna

Amuchastegui

Cossetti

et al. 2006

The Journal of Immunology

119

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“…The initial demonstration that 1,25-(OH) 2 D 3 is an antiproliferative, prodifferentiating agent for certain cell types in vivo and many cell lines in vitro ( 152 ), coupled with the fact that cancer cell studies have showed decreased CYP27B1 and increased CYP24A1 expression in prostatic, colonic, and breast cell lines as they progress toward a more tumorigenic phenotype ( 97,(153)(154)(155)(156), has caused Of these, only IIH has unknown etiology and, until recently, had no gene locus assigned to it ( 164,165 ). In 2011, Schlingmann et al ( 166 ) demonstrated that loss-offunction mutations of CYP24A1 were an underlying cause of IIH in nine families of German, Turkish, and Russian origin.…”

Section: Downloaded Frommentioning

confidence: 99%

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

395

292

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signal transduction system, the DBP-knockout mouse is normocalcemic and exhibits normal tissue distribution of vitamin D metabolites and vitamin D action despite exhibiting very low blood levels of 1,25-(OH) 2 D 3 . This unexpected phenotype raised questions about DBP's exact role: essential transporter or buffer against toxicity ( 7,8 ). Work performed on the 25-hydroxylases over the past four decades in humans and a variety of animal species has revealed that several cytochrome P450 enzymes 2 (CYP), such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, and perhaps others, are capable of 25-hydroxylation of vitamin D 3 or related compounds. These CYPs can be referred to as vitamin D 3 -25-hydroxylases, and it is CYP2R1 that is emerging as the physiologically relevant enzyme ( 9 ). On the other hand, there is no ambiguity over the second step of 1 ␣ -hydroxylation or the 25-OH-D 3 -1 ␣ -hydroxylase enzyme responsible, which is carried by a single cytochrome P450 2 named CYP27B1 ( 10-12 ). The inactivation of vitamin D is carried out by the mitochondrial enzyme, 25-hydroxyvitamin D 3 -24-hydroxylase, fi rst described in the early 1970s and initially believed to be involved solely in the renal 24-hydroxylation of 25-OH-D 3 ( 13 ). Work performed over the last 35 years has shown that 24-hydroxylase enzyme activity is the result of CYP24A1 ( 5, 14 ). CYP24A1 catalyzes the conversion of both 25-OH-D 3 and 1,25-(OH) 2 D 3 into a series of 24-and 23-hydroxylated products targeted for excretion along well-established pathways culminating in the water-soluble biliary metabolite calcitroic acid or a 26,23-lactone.This article assembles the most currently pertinent literature on the activating and inactivating enzymes of vitamin D metabolism and highlights protein structure and enzymatic properties, crystal structures, gene organization, and The activation of vitamin D 3 is accomplished by sequential steps of 25-hydroxylation to produce the main circulating form, 25-hydroxyvitamin D (25-OH-D 3 ), followed by 1 ␣ -hydroxylation to the hormonal form, 1 ␣ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( 1 ) ( Fig. 1 ). The initial step of 25-hydroxylation occurs in the liver ( 2 ), and the second step occurs both in the kidney and extrarenal sites ( 3, 4 ). The fat-soluble vitamin D and its metabolites are transported from one tissue to another on the vitamin D-binding protein (DBP), which shows different affi nity for the individual metabolites ( 5 ). The cell-surface receptor megalin-cubilin is thought to facilitate the endocytosis of a DBP-bound 25-OH-D 3 into a number of cell types, especially kidney cells ( 6 ). While it is widely believed that DBP is an essential component of the vitamin D

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“…Thus, over-expression of 24-hydroxylase may further abrogate growth control mediated by 1a,25(OH) 2 D 3 , via target cell inactivation of the hormone. It has therefore been proposed that breast cancer is associated with low circulating concentrations of 25OH-D, arising as a result of reduced exposure to sunlight, altered dietary patterns and impaired generation of 1a,25(OH) 2 D 3 within breast tissue (51,(117)(118)(119)(120)(121) .…”

Section: Epidemiological Evidencementioning

confidence: 99%

The vitamin D receptor in cancer

2008

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Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1a,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics. The cancer burdenThe impact of cancer continues to be one of the greatest burdens in the developed world and is also increasingly impacting on the developing world. Approximately 1 . 5 million individuals will die from breast, colon or prostate cancer this year, and the total number of deaths from cancer accounts for 13 % of all deaths worldwide and for one in every four deaths in the UK and USA (1) . The impact is also economic; $280 · 10 9 is spent annually worldwide on the treatment of patients. Many cancers are however preventable, and through lifestyle choices such as smoking, diet and exercise the worldwide incidence of cancer could be cut by 40 % (2,3) . Major risk factors for cancer DietRecently, the appreciation of the impact of diet on cancer has come to the fore, with a number of studies establishing unequivocal relationships between diet and cancer initiation and progression. Reflecting the accumulation of these data, the WHO has now stated that diet forms the secondmost preventable cause of cancer (after smoking) (3) . This impact will rise further as a result of demographic factors, and quite possibly because of changing dietary habits worldwide, which will contribute further to the projected increase in cancer incidence in developing nations. Highprofile malignancies such as breast, prostate, and colon cancer typify this scenario, in which the aetiology of the disease reflects the cumulative impact of dietary factors over an individual's lifetime (4)(5)(6) . The relationship between diet and disease is already exploited clinically, e.g. in the Selenium and Vitamin E Cancer Prevention Trial to assess the chemoprevention potential of vitamin E ...

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Prostatic 25‐hydroxyvitamin D‐1α‐hydroxylase and its implication in prostate cancer

Cited by 125 publications

References 23 publications

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

Cytochrome P450-mediated metabolism of vitamin D

The vitamin D receptor in cancer

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