The role of Vitamin D3 metabolism in prostate cancer

https://doi.org/10.1016/j.jsbmb.2004.10.007Get rights and content

Abstract

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 1α-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 1α-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.

Introduction

Although Vitamin D is still best known from its role as a regulator of calcium and phosphorus balance, there is an increasing interest in other hormonal effects of Vitamin D in all organs and cells of the body. Regulation of many cell types with respect to their function, growth, differentiation and apoptosis are controlled by Vitamin D.

Vitamin D was originally found as a plant-derived antirachitic agent, which was named Vitamin D2 (ergosterol). However, the subsequent characterization of structure and intrinsic synthesis of animal form, termed Vitamin D3 (cholecalciferol), which formed a basis of the hormonal Vitamin D [2], [3]. In human system, the production of Vitamin D3 in skin is crucial, since nutrional supply of Vitamin D3 as well as Vitamin D2 is limited. The production of Vitamin D3 begins from plasma membrane of skin cells where 7-dehydrocholesterol is photolyzed by UV light to produce previtamin D3 which undergoes thermal isomerization to Vitamin D3. The synthesis of previtamin D3 and Vitamin D3 are self-controlled processes since further absorption of UV light causes isomerizations of these compounds to yield inactive products [4]. Conversion of 7-dehydrocholesterol to previtamin D3 is decreased to less than half in elderly people [5]. From skin Vitamin D3 enters to circulation where all Vitamin D compounds are mainly bound to Vitamin D binding protein (DBP) [6].

In the body, both Vitamin D2 and D3 undergo similar activation processes, which are prerequisite for their biological activity. Basic activation route of Vitamin D (hereafter Vitamin D3) involves two successive hydroxylations catalysed by cytochrome p450 enzymes (Fig. 1). The first hydroxylation at the position C-25 occurs in liver by the mitochondrial sterol 27-hydroxylase (27-hydroxylase; CYP27A1) to yield 25-hydroxyvitamin D3 (25OHD3), which is the major circulating form of Vitamin D [7]. Second hydroxylation at position C-1 occurring in kidney by 25-hydroxyvitamin D31α-hydroxylase (1α-hydroxylase; CYP 27B1) produces the most active form of Vitamin D namely 1α,25-dihydroxyvitamin D3(1α,25(OH)2D3) [8]. The serum values for 1α,25(OH)2D3 are approximately 1000 -fold less to that of 25OHD3. The above described route of Vitamin D activation has later been complicated by the studies revealing several tissue types to express 1α-hydroxylase and, thus, being capable for extrarenal production of 1α,25(OH)2D3 [9]. Among this skin has been shown to express all enzymes needed to exhibit autonomous production 1α,25(OH)2D3 [10]. In addition, there is evidence that it is actually microsomal 25-hydroxylase activity that plays a major role for production of 25OHD3 in liver [11]. Recently, a novel enzyme displaying microsomal 25–hydroxylase activity has been characterized in human by Cheng et al. [12].

Inactivation of 1α,25(OH)2D3 and 25OHD3 is catalyzed by mitochondrial 25-hydroxyvitamin D324-hydroxylase (24-hydroxylase; CYP24) [13]. This enzyme sequentially hydroxylases 25OHD3 or 1α,25(OH)2D3 starting at C23 or C24 positions finally yielding more hydrophilic product for excretion [14]. 24-Hydroxylase is abundantly expressed in kidney but most probably all Vitamin D target cells express the enzyme [15]. In kidney, 1α,25(OH)2D3 itself among many other regulatory factors is involved in coordination its own synthesis and inactivation being strong inducer of 24-hydroxylase while inhibiting 1α-hydroxylase expression [15], [16].

The hallmark in functional study of Vitamin D action was cloning of the respective receptor for 1α,25(OH)2D3, Vitamin D receptor (VDR) which was found to act as ligand-inducible transcription factor and mediate effects of Vitamin D on target gene transcription [17], [18]. The studies revealing ubiquitous expression of VDR provided evidence for its central role in pleiotropic action of Vitamin D [19], [20]. Later works including structural characterization of DNA binding regions for VDR and discovering of retinoid X receptor (RXR) as dimerization counterpart of VDR provided a base for current model of genomic action of VDR [21], [22]. On the other hand, action of 1α,25(OH)2D has appeared to involve also rapid nongenomic effects including activation of protein kinase C and MAP-kinase [23]. These effects occurs within minutes after hormone administration and arise from cell plasma membrane by yet poorly understood mechanisms which may involve novel receptor systems for Vitamin D metabolites. Interestingly, both genomic and nongenomic signalling pathways of 1α,25(OH)2D3 has been, recently, shown to meet in controlling transcriptional induction of the rat 24-hydroxylase gene [24]. On the other hand, our laboratory has provided new evidence for biological activity of 25OHD3 with reference to transcriptional induction of 24-hydroxylase expression in human prostatic stromal cells [25].

Section snippets

Growth regulation by Vitamin D in normal and malignant prostate

The active form of Vitamin D, 1α,25(OH)2D3, in addition to its long recognized role in calcium homeostasis, has been identified as a secosteroid hormone with antiproliferative effect on normal and malignant cells and, thus, it and its less calcemic analogues are recommended as potential compounds for cancer treatment. The antiproliferative function of 1α,25(OH)2D3 is thought to be exerted mainly through nuclear Vitamin D receptor-mediated pathway to control the target gene expression, resulting

25-Hydroxyvitamin D31α-hydroxylase

Human prostate cancer cell lines and primary cultures of noncancerous prostatic cells have 1α-hydroxylase activity [56]. A reduced 1α-hydroxylase activity in prostate cancer cells compared with cells derived from normal or benign prostatic hyperplasia tissues was observed [57], which seems to be due to a decreased promoter activity [54]. In colon cancer, the correlation between the differentiation grade and 1α-hydroxylase mRNA content remains controversial. One study reported that poorly

New 25OH D3 hormonal system

We, recently, showed evidence for a new Vitamin D endocrine system [25]. 25OHD3 seems to be an active hormone in human prostatic stromal cells with respect to Vitamin D3 response gene regulation and cell growth inhibition [25]. Our finding suggests that, in physiological concentration, 1α,25(OH)2D3 is inactive whereas 25OHD3 is active hormone in the prostate cells (Fig. 3). In our primary cultures of human prostatic stromal cells, 25OHD3 at a physiological concentration of 250 nM exhibited a

Inhibitors for 24-hydroxylase in the treatment of prostate cancer

As mentioned above, 24-hydroxylase controls the first inactivation step of 1α,25(OH)2D3 and 25OHD3, therefore an inhibition of 24-hydroxylase activity could be beneficial and enhance Vitamin D action. The widely used inhibitors are antifungal imidazole derivatives, such as ketoconazole, liarozole and newly identified VID400. Imidazole derivatives, ketoconazole and liarozole, inhibit steroidogenesis by interfering with cytochrome P450 enzyme system [79]. They are promising in prostate cancer

Phytoestrogens—novel modulators of Vitamin D metabolism in the prostate

Phytoestrogens have been shown to have a beneficial effect on cancers in both in vitro [86], [87], [88] and in epidemiological studies [89], [90]. Recently, their inhibiting effect on Vitamin D metabolizing enzymes has also been established [91], [92], [93].

Phytoestrogens are a subclass of flavonoids, phenolic compounds present in all plants. The two main groups of phytoestrogens are the isoflavonoids and the lignans. Isoflavonoids, such as genistein, daidzein and glycitein, can be found in

References (114)

  • S. Colnot et al.

    Identification of DNA sequences that bind retinoid X receptor-1,25(OH)2D3-receptor heterodimers with high affinity

    Mol. Cell. Endocrinol.

    (1995)
  • A.W. Norman et al.

    Update on biological actions of 1alpha,25(OH)2-Vitamin D3 (rapid effects) and 24R,25(OH)2-Vitamin D3

    Mol. Cell. Endocrinol.

    (2002)
  • P.P. Dwivedi et al.

    Role of MAP kinases in the 1,25-dihydroxyvitamin D3-induced transactivation of the rat cytochrome P450C24 (CYP24) promoter. Specific functions for ERK1/ERK2 and ERK5

    J. Biol. Chem.

    (2002)
  • T. Ylikomi et al.

    Antiproliferative action of Vitamin D

    Vitam. Horm.

    (2002)
  • M. Kivineva et al.

    Localization of 1,25-dihydroxyvitamin D3 receptor (VDR) expression in human prostate

    J. Steroid Biochem. Mol. Biol.

    (1998)
  • J.L. Osborn et al.

    Phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer

    Urol. Oncol.

    (1995)
  • R.S. Fife et al.

    Effects of Vitamin D3 on proliferation of cancer cells in vitro

    Cancer Lett.

    (1997)
  • T. Hsieh et al.

    Induction of apoptosis and altered nuclear/cytoplasmic distribution of the androgen receptor and prostate-specific antigen by 1alpha,25-dihydroxyvitamin D3 in androgen-responsive LNCaP cells

    Biochem. Biophys. Res. Commun.

    (1997)
  • E.S. Yang et al.

    Vitamin D inhibits G1 to S phase progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm

    J. Biol. Chem.

    (2003)
  • B.J. Boyle 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

    J. Urol.

    (2001)
  • S. Qiao et al.

    Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells

    J. Steroid Biochem. Mol. Biol.

    (2003)
  • D. Krill et al.

    Differential effects of Vitamin D on normal human prostate epithelial and stromal cells in primary culture

    Urology

    (1999)
  • P. Bareis et al.

    25-hydroxy-vitamin d metabolism in human colon cancer cells during tumor progression

    Biochem. Biophys. Res. Commun.

    (2001)
  • V. Tangpricha et al.

    25-Hydroxyvitamin D-1alpha-hydroxylase in normal and malignant colon tissue

    Lancet

    (2001)
  • T. Monkawa et al.

    Identification of 25-hydroxyvitamin D31alpha-hydroxylase gene expression in macrophages

    Kidney Int.

    (2000)
  • J.A. Johnson et al.

    Age and gender effects on 1,25-dihydroxyvitamin D3-regulated gene expression

    Exp. Gerontol.

    (1995)
  • B.R. Konety et al.

    Evaluation of intraprostatic metabolism of 1,25-dihydroxyvitamin D(3) (calcitriol) using a microdialysis technique

    Urology

    (2002)
  • J. Rungby et al.

    Distribution of hydroxylated Vitamin D metabolites [25OHD3 and 1,25(OH)2D3] in domestic pigs: evidence that 1,25(OH)2D3 is stored outside the blood circulation?

    Comp. Biochem. Physiol. Comp. Physiol.

    (1993)
  • T. Eichenberger et al.

    Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells

    J. Urol.

    (1989)
  • J. Zhao et al.

    Enhancement of antiproliferative activity of 1alpha,25-dihydroxyvitamin D3 (analogs) by cytochrome P450 enzyme inhibitors is compound- and cell-type specific

    J. Steroid Biochem. Mol. Biol.

    (1996)
  • D.M. Peehl et al.

    Preclinical activity of ketoconazole in combination with calcitriol or the Vitamin D analogue EB 1089 in prostate cancer cells

    J. Urol.

    (2002)
  • D. Ingram et al.

    Case-control study of phyto-oestrogens and breast cancer

    Lancet

    (1997)
  • H. Farhan et al.

    Genistein inhibits Vitamin D hydroxylases CYP24 and CYP27B1 expression in prostate cells

    J. Steroid Biochem. Mol. Biol.

    (2003)
  • H. Farhan et al.

    Isoflavonoids inhibit catabolism of Vitamin D in prostate cancer cells

    J. Chromatogr. B Anal. Technol. Biomed. Life Sci.

    (2002)
  • H. Adlercreutz et al.

    Dietary phytoestrogens and cancer: in vitro and in vivo studies

    J. Steroid Biochem. Mol. Biol.

    (1992)
  • M.F. Holick et al.

    Photosynthesis of previtamin D3 in human skin and the physiologic consequences

    Science

    (1980)
  • M.F. Holick et al.

    Skin as the site of Vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol (1,25-dihydroxyvitamin D3) for treatment of psoriasis

    Arch. Dermatol.

    (1987)
  • N.E. Cooke et al.

    Serum Vitamin D-binding protein is a third member of the albumin and alpha fetoprotein gene family

    J. Clin. Invest.

    (1985)
  • D.E. Lawson et al.

    Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism

    Nature

    (1971)
  • M. Hewison et al.

    1alpha-hydroxylase and the action of Vitamin D [In Process Citation]

    J. Mol. Endocrinol.

    (2000)
  • T. Sakaki et al.

    Dual metabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24

    Eur. J. Biochem.

    (2000)
  • D.P. McDonnell et al.

    Molecular cloning of complementary DNA encoding the avian receptor for Vitamin D

    Science

    (1987)
  • A.R. Baker et al.

    Cloning and expression of full-length cDNA encoding human Vitamin D receptor

    Proc. Natl. Acad. Sci. U.S.A.

    (1988)
  • T.L. Clemens et al.

    Immunocytochemical localization of the 1,25-dihydroxyvitamin D3 receptor in target cells

    Endocrinology

    (1988)
  • U. Berger et al.

    Immunocytochemical detection of 1,25-dihydroxyvitamin D receptors in normal human tissues

    J. Clin. Endocrinol. Metab.

    (1988)
  • P.N. MacDonald et al.

    Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene

    Mol. Cell. Biol.

    (1993)
  • Y.R. Lou et al.

    25-Hydroxyvitamin D3 is an active hormone in human primary prostatic stromal cells

    FASEB J.

    (2004)
  • D.M. Peehl et al.

    Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells

    Cancer Res.

    (1994)
  • G.J. Miller et al.

    The human prostatic carcinoma cell line LNCaP expresses biologically active, specific receptors for 1 alpha,25-dihydroxyvitamin D3

    Cancer Res.

    (1992)
  • R.J. Skowronski et al.

    Vitamin D and prostate cancer: 1,25 dihydroxyvitamin D3 receptors and actions in human prostate cancer cell lines

    Endocrinology

    (1993)
  • Cited by (68)

    • The new insight on the regulatory role of the vitamin D3 in metabolic pathways characteristic for cancerogenesis and neurodegenerative diseases

      2015, Ageing Research Reviews
      Citation Excerpt :

      Experimental therapy on patients with prostate cancer showed that the combination of 1,25(OH)2D3 and non-steroidal anti-inflammatory drugs such as non-selective naproxen, results in a synergistic inhibition of the growth, angiogenesis, invasion, and metastasis of cancer cells and offers a potential therapeutic strategy (Srinivas and Feldman, 2009). In prostate cells, vitamin D3 increases the expression of mitogen-activated protein kinase phosphatase 5 (MAPK5) resulting in attenuation of the production of pro-inflammatory cytokines and alters NFκB signalling in colon cancer cells (Lou et al., 2004). Cell culture and in vivo data in mice strongly suggest that dietary calcitriol would play a beneficial role in the prevention or treatment of estrogen receptor positive breast cancer in women probably by antiestrogenic properties of calcitriol and new derivatives of vitamin D3 (Narvaez and Welsh, 2001).

    • Bioavailable dietary phosphate, a mediator of cardiovascular disease, may be decreased with plant-based diets, phosphate binders, niacin, and avoidance of phosphate additives

      2014, Nutrition
      Citation Excerpt :

      Additionally, calcitriol can exert anti-inflammatory effects on vascular macrophages; however, calcitriol of autocrine origin (regulated by circulating calcidiol) seems likely to play the chief role in this regard [60–62]. Similarly, whereas serum calcitriol has the potential to decrease risk for cancer in certain vitamin D-responsive epithelia, autocrine calcitriol is thought to make a more important contribution to vitamin D activity in these tissues [63–65]. The possibility that serum calcitriol might modestly modulate cancer risk in the context of poor vitamin D status (and hence low calcidiol levels) requires further evaluation [66]; so far, the effect of serum phosphate on cancer risks has received minimal study.

    View all citing articles on Scopus
    View full text