Abstract
There is substantial interest in whether vitamin D signaling plays a role in reducing risk for prostate cancer and in its use as a therapeutic target in prostate cancer. Vitamin D is synthesized in the skin through a UVB-mediated reaction and subsequently hydroxylated to form 1,25-dihydroxyvitamin D3, the ligand for the vitamin D receptor (VDR), a hormone activated transcription factor. Epidemiological studies correlating prostate cancer risk with reduced exposure to sunlight have suggested that vitamin D reduces risk, but the conclusions from studies of vitamin D metabolites have been variable. Similarly, despite promising results in preclinical studies, attempts to target VDR clinically have been less successful. This chapter reviews what is known regarding the actions of VDR in prostate and in prostate cancers and the evidence for activation of VDR as a strategy to reduce risk and/or treat prostate cancer. The chapter summarizes the evidence for a role in reducing prostate cancer risk and discusses the possibility that aberrant vitamin D metabolism contributes to the difficulties in correlating serum vitamin D metabolites with the level of VDR activation in cells. Also discussed are other mechanisms for resistance to the beneficial actions of VDR and strategies to optimize VDR activity.
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Christakos S, DeLuca HF (2011) Vitamin D: is there a role in extraskeletal health? Endocrinology 152:2930–2936
Touvier M, Chan DS, Lau R, Aune D, Vieira R, Greenwood DC, Kampman E, Riboli E, Hercberg S, Norat T (2011) Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and colorectal cancer risk. Cancer Epidemiol Biomarker Prev 20:1003–1016
Haussler MR, Whitfield GK, Haussler CA, Hsieh J-C, Thompson PD, Selznick SH, Dominguez CE, Jurutka PW (1998) The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Min Res 13:325–349
Pike JW, Meyer MB, Martowicz ML, Bishop KA, Lee SM, Nerenz RD, Goetsch PD (2010) Emerging regulatory paradigms for control of gene expression by 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 121:130–135
Christakos S, Ajibade DV, Dhawan P, Fechner AJ, Mady LJ (2010) Vitamin D: metabolism. Endocrinol Metab Clin North Am 39:243–253
Jones G (2008) Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 88:582S–586S
Dusso AS, Kamimura S, Gallieni M, Zhong M, Negrea L, Shapiro S, Slatopolsky E (1997) gamma-Interferon-induced resistance to 1,25-(O)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses. J Clin Endocrinol Metab 82:2222–2232
Akiyoshi-Shibata M, Sakaki T, Ohyama Y, Noshiro M, Okuda K, Yabusaki Y (1994) Further oxidation of hydroxycalcidiol by calcidiol 24-hydroxylase. A study with the mature enzyme expressed in Escherichia coli. Eur J Biochem 224:335–343
Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF (1998) Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarker Prev 7:391–395
Hsu JY, Feldman D, McNeal JE, Peehl DM (2001) Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res 61:2852–2856
Khorchide M, Lechner D, Cross HS (2005) Epigenetic regulation of vitamin D hydroxylase expression and activity in normal and malignant human prostate cells. J Steroid Biochem Mol Biol 93:167–172
Chen TC, Wang L, Whitlatch LW, Flanagan JN, Holick MF (2003) Prostatic 25-Âhydroxyvitamin D-1α-hydroxylase and its implication in prostate cancer. J Cell Biochem 88:315–322
Ma JF, Nonn L, Campbell MJ, Hewison M, Feldman D, Peehl DM (2004) Mechanisms of decreased vitamin D 1alpha-hydroxylase activity in prostate cancer cells. Mol Cell Endocrinol 221:67–74
Maas RM, Reus K, Diesel B, Steudel WI, Feiden W, Fischer U, Meese E (2001) Amplification and expression of splice variants of the gene encoding the P450 cytochrome 25-Âhydroxyvitamin D(3) 1, alpha-hydroxylase (CYP27B1) in human malignant glioma. Clin Cancer Res 7:868–875
Mitschele T, Diesel B, Friedrich M, Meineke V, Maas RM, Gärtner BC, Kamradt J, Meese E, Tilgen W, Reichrath J (2004) Analysis of the vitamin D system in basal cell carcinomas (BCCs). Lab Invest 84:693–702
Fischer D, Thomé M, Becker S, Cordes T, Diedrich K, Friedrich M, Thill M (2009) 25-Hydroxyvitamin D3 1alpha-hydroxylase splice variants in benign and malignant ovarian cell lines and tissue. Anticancer Res 29:3627–3633
Seifert M, Tilgen W, Reichrath J (2009) Expression of 25-hydroxyvitamin D-1alpha-hydroxylase (1alphaOHase, CYP27B1) splice variants in HaCaT keratinocytes and other skin cells: modulation by culture conditions and UV-B treatment in vitro. Anticancer Res 29:3659–3667
Cordes T, Diesing D, Becker S, Fischer D, Diedrich K, Friedrich M (2007) Expression of splice variants of 1alpha-hydroxylase in mcf-7 breast cancer cells. J Steroid Biochem Mol Biol 103:326–329
Chung I, Karpf AR, Muindi JR, Conroy JM, Nowak NJ, Johnson CS, Trump DL (2007) Epigenetic silencing of CYP24 in tumor-derived endothelial cells contributes to selective growth inhibition by calcitrol. J Biol Chem 282:8704–8714
Lou YR, Tuohimaa P (2006) Androgen enhances the antiproliferative activity of vitamin D3 by suppressing 24-hydroxylase expression in LNCaP cells. J Steroid Biochem Mol Biol 99:44–49
Lou YR, Nazarova N, Talonpoika R, Tuohimaa P (2005) 5α-dihydrotestosterone inhibits 1α,25-dihydroxyvitamin D3-induced expression of CYP24 in human prostate cancer cells. Prostate 63:222–230
Farhan H, Wahala K, Cross HS (2003) Genistein inhibits Vitamin D hydroxylases CYP24 and CYP27B1 expression in prostate cells. J Steroid Biochem Mol Biol 84:423–429
Swami S, Krishnan AV, Peehl DM, Feldman D (2005) Genistein potentiates the growth inhibitory effects of 1,25-dihydroxyvitamin D3 in DU145 human prostate cancer cells: role of the direct inhibition of CYP24 enzyme activity. Mol Cell Endocrinol 241:49–61
Holick MF, Matsuoka LY, Wortsman J (1989) Age, vitamin D, and solar ultraviolet. Lancet 2:1104–1105
Giovannucci E (2008) Vitamin D status and cancer incidence and mortality. Adv Exp Med Biol 624:31–42
Schwartz GG, Hanchette CL (2006) UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control 17:1091–1101
John EM, Koo J, Schwartz GG (2007) Sun exposure and prostate cancer risk: evidence for a protective effect of early-life exposure. Cancer Epidemiol Biomarker Prev 16:1283–1286
Schwartz GG, Hulka BS (1990) Is vitamin D deficiency a risk factor for prostate cancer? (hypothesis). Anticancer Res 10:1307–1312
John EM, Schwartz GG, Koo J, Van Den Berg D, Ingles SA (2005) Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer. Cancer Res 65:5470–5479
Loke TW, Sevfi D, Khadra M (2011) Prostate cancer incidence in Australia correlates inversely with solar radiation. BJU Int 108:66–70
Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P (2000) Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 11:847–852
Ahn J, Peters U, Albanes D, Purdue MP, Abnet CC, Chatterjee N, Horst RL, Hollis BW, Huang WY, Shikany JM, Hayes RB (2008) Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 100:796–804
Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G, Stattin P, Harvei S, Hakulinen T, Luostarinen T, Dillner J, Lehtinen M, Hakama M (2004) Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 108:104–108
Shui IM, Mucci LA, Kraft P, Tamimi RM, Lindstrom S, Penney KL, Nimptsch K, Hollis BW, Dupre N, Platz EA, Stampfer MJ, Giovannucci E (2012) Vitamin D-related genetic variation, plasma vitamin D and risk of lethal prostate cancer: a prospective nested case-control study. J Natl Cancer Inst 104:690–699
Blutt SE, Allegretto EA, Pike JW, Weigel NL (1997) 1,25-dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growth of LNCaP prostate cells and cause accumulation of cells in G1. Endocrinology 138:1491–1497
Skowronski RJ, Peehl DM, Feldman D (1993) Vitamin D and prostate cancer: 1,25 dihydroxyvitamin D3 receptors and actions in human prostate cancer cell lines. Endocrinology 132:1952–1960
Peehl DM, Skowronski RJ, Leung GK, Wong ST, Stamey TA, Feldman D (1994) Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res 54:805–810
Welsh J, Wietzke JA, Zinser GM, Smyczek S, Romu S, Tribble E, Welsh JC, Byrne B, Narvaez CJ (2002) Impact of the Vitamin D3 receptor on growth-regulatory pathways in mammary gland and breast cancer. J Steroid Biochem Mol Biol 83:85–92
Yang ES, Burnstein KL (2003) 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 278:46862–46868
Blutt SE, McDonnell TJ, Polek TC, Weigel NL (2000) Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. Endocrinology 141:10–17
Campbell MJ, Elstner E, Holden S, Uskokovic M, Koeffler HP (1997) Inhibition of proliferation of prostate cancer cells by a 19-NOR-Hexafluoride vitamin D3 analogue involves the induction of p21 (WAF1), p27 (KIP1) and E-Cadherin. J Mol Endocrinol 19:15–27
Kovalenko PL, Zhang Z, Yu JG, Li Y, Clinton SK, Fleet JC (2011) Dietary vitamin D and vitamin D receptor level modulate epithelial cell proliferation and apoptosis in the prostate. Cancer Prev Res 4:1617–1625
Banach-Petrosky W, Ouyang X, Gao H, Nader K, Ji Y, Suh N, DiPaola RS, Abate-Shen C (2006) Vitamin D inhibits the formation of prostatic intraepithelial neoplasia in Nkx3.1;Pten mutant mice. Clin Cancer Res 12:5895–5901
Swami S, Krishnan AV, Wang JY, Jensen K, Horst R, Albertelli MA, Feldman D (2012) Dietary vitamin D3 and 1,25-dihydroxyvitamin D3 (calcitriol) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer. Endocrinology 153:2576–2587
Blutt SE, Polek TC, Stewart LV, Kattan MW, Weigel NL (2000) A calcitriol analogue, EB1089, inhibits the growth of LNCaP tumors in nude mice. Cancer Res 60:779–782
Polek TC, Murthy S, Blutt SE, Boehm MF, Zou A, Weigel NL, Allegretto EA (2001) Novel nonsecosteroidal vitamin D receptor modulator inhibits the growth of LNCaP xenograft tumors in athymic mice without increased serum calcium. Prostate 49:224–233
Okamoto R, Delansorne R, Wakimoto N, Doan NB, Akagi T, Shen M, Ho QH, Said JW, Koeffler HP (2012) Inecalcitol, an analog of 1α,25(OH)(2) D(3), induces growth arrest of androgen-dependent prostate cancer cells. Int J Cancer 130:2464–2473
Bhatia V, Saini MK, Shen X, Bi LX, Qiu S, Weigel NL, Falzon M (2009) EB1089 inhibits the parathyroid hormone-related protein-enhanced bone metastasis and xenograft growth of human prostate cancer cells. Mol Cancer Ther 8:1787–1798
Peleg S, Khan F, Navone NM, Cody DD, Johnson EM, Van Pelt CS, Posner GH (2005) Inhibition of prostate cancer-meditated osteoblastic bone lesions by the low-calcemic analog 1alpha-hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy vitamin D3. J Steroid Biochem Mol Biol 97:203–211
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644–648
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947
Zong Y, Xin L, Goldstein AS, Lawson DA, Teitell MA, Witte ON (2009) ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Proc Natl Acad Sci USA 106:12465–12470
Koh CM, Gurel B, Sutcliffe S, Aryee MJ, Schultz D, Iwata T, Uemura M, Zeller KI, Anele U, Zheng Q, Hicks JL, Nelson WG, Dang CV, Yegnasubramanian S, de Marzo AM (2011) Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene. Am J Pathol 178:1824–1834
Iwata T, Schultz D, Hicks J, Hubbard GK, Mutton LN, Lotan TL, Bethel C, Lotz MT, Yegnasubramanian S, Nelson WG, Dang CV, Xu M, Anele U, Koh CM, Bieberich CJ, de Marzo AM (2010) MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells. PLoS ONE 5:e9427
Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, Thomas GV, Sawyers CL (2003) Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4:223–238
Thalmann GN, Anezinis PE, Chang S-M, Zhau HE, Kim EE, Hopwood VL, Pathak S, Von Eschenbach AC, Chung LWK (1994) Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res 54:2577–2581
Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J (1998) Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 58:2720–2723
van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, Nordeen SK, Miller GJ, Lucia MS (2003) Molecular characterization of human prostate carcinoma cell lines. Prostate 57:205–225
Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J, Dedhar S (2000) Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci USA 97:3207–3212
Bookstein R, Shew J-Y, Chen P-L, Scully P, Lee W-H (1990) Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated Rb gene. Science 247:712–715
Zhuang SH, Burnstein KL (1998) Antiproliferative effect of 1α,25-dihydroxyvitamin D3 in human prostate cancer cell line LNCaP involves reduction of cyclin-dependent kinase 2 activity and persistent G1 accumulation. Endocrinology 139:1197–1207
Polek TC, Stewart LV, Ryu EJ, Cohen MB, Allegretto EA, Weigel NL (2003) p53 is required for 1,25-dihydroxyvitamin D3-induced G0 arrest, but is not required for G1 accumulation or apoptosis of LNCaP prostate cancer cells. Endocrinology 144:50–60
Sala A, Nicolaides NC, Engelhard A, Bellon T, Lawe DC, Arnold A, Graña X, Giordano A, Calabretta B (1994) Correlation between E2F-1 requirement in the S phase and E2F-1 transactivation of cell cycle-related genes in human cells. Cancer Res 54:1402–1406
Chellappan GF, Hiebert S, Mudryj M, Horowitz JM, Nevins JR (1991) The E2F transcription factor is a cellular target for the RB protein. Cell 65:1053–1061
Lundberg AS, Weinberg RA (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol 18:753–761
Thorne JL, Maguire O, Doig CL, Battaglia S, Fehr L, Sucheston LE, Heinaniemi M, O’Neill LP, McCabe CJ, Turner BM, Carlberg C, Campbell MJ (2011) Epigenetic control of a VDR-Âgoverned feed-forward loop that regulates p21(waf1/cip1) expression and function in non-Âmalignant prostate cells. Nucleic Acids Res 39:2045–2056
Kovalenko PL, Zhang Z, Ciu M, Clinton SK, Fleet JC (2010) 1,25-dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-Âtransformed prostate epithelial cell line, RWPE1. BMC Genomics 11:26
Flores O, Wang Z, Knudsen KE, Burnstein KL (2010) Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition. Endocrinology 151:896–908
Washington MN, Kim JS, Weigel NL (2011) 1α,25-dihydroxyvitamin D3 inhibits C4-2 prostate cancer cell growth via a retinoblastoma protein (Rb)-independent G1 arrest. Prostate 71:98–110
Bartek J, Lukas J (2001) Pathways governing G1/S transition and their response to DNA damage. FEBS Lett 490:117–122
Dang CV (2012) MYC on the path to cancer. Cell 149:22–35
Rohan JN, Weigel NL (2009) 1Alpha,25-dihydroxyvitamin D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells. Endocrinology 150:2046–2054
Meyer MB, Goetsch PD, Pike JW (2012) VDR/RXR and TCF4/β-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression. Mol Endocrinol 26:37–51
Ikezoe T, Gery S, Yin D, O’Kelly J, Binderup L, Lemp N, Taguchi H, Koeffler HP (2005) CCAAT/enhancer-binding protein delta: a molecular target of 1,25-dihydroxyvitamin D3 in androgen-responsive prostate cancer LNCaP cells. Cancer Res 65:4762–4768
Si J, Yu X, Zhang Y, DeWille JW (2010) Myc interacts with Max and Miz1 to repress C/EBPdelta promoter activity and gene expression. Mol Cancer 9:92
Flores O, Burnstein KL (2010) GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells. Endocrinology 151:4654–4664
Hsieh T, Wu JM (1997) 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 Comm 235:539–544
Guzey M, Kitada S, Reed JC (2002) Apoptosis induction by 1α,25-dihydroxyvitamin D3 in prostate cancer. Mol Cancer Ther 1:667–677
Berkovich L, Ben-Shabat S, Sintov AC (2010) Induction of apoptosis and inhibition of prostate and breast cancer growth by BGP-15, a new calcipotriene-derived vitamin D3 analog. Anticancer Drugs 21:609–618
Hsing AY, Kadomatsu K, Bonham MJ, Danielpour D (1996) Regulation of apoptosis induced by transforming growth factor-beta1 in nontumorigenic rat prostatic epithelial cell lines. Cancer Res 56:5146–5149
Landström M, Heldin NE, Bu S, Hermansson A, Itoh S, ten Dijke P, Heldin CH (2000) Smad7 mediates apoptosis induced by transforming growth factor beta in prostatic carcinoma cells. Curr Biol 10:535–538
Lee C, Sintich SM, Mathews EP, Shah AH, Kundu SD, Perry KT, Cho JS, Ilio KY, Cronauer MV, Janulis L, Sensibar JA (1999) Transforming growth factor-beta in benign and malignant prostate. Prostate 39:285–290
Dennler S, Goumans MJ, ten Dijke P (2002) Transforming growth factor beta signal Âtransduction. J Leukoc Biol 71:731–740
Murthy S, Weigel NL (2004) 1α,25-Dihydroxyvitamin D3 induced growth inhibition of PC-3 prostate cancer cells requires an active transforming growth factor beta signaling pathway. Prostate 59:282–291
Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano JM, Pollak M, Giovannucci E (2002) Insulin-Âlike growth factor-1 (IGF-1) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 94:1099–1106
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M (1998) Plasma insulin-like growth factor-1 and prostate cancer risk: a prospective study. Science 279:563–566
Mehta HH, Gao Q, Galet C, Paharkova V, Wan J, Said J, Sohn JJ, Lawson G, Cohen P, Cobb LJ, Lee KW (2011) IGFBP-3 is a metastasis suppression gene in prostate cancer. Cancer Res 71:5154–5163
Krishnan AV, Shinghal R, Raghavachari N, Brooks JD, Peehl DM, Feldman D (2004) Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays. Prostate 59:243–251
Peng L, Malloy PJ, Feldman D (2004) Identification of a functional vitamin D response element in the human insulin-like growth factor binding protein-3 promoter. Mol Endocrinol 18:1109–1119
Boyle BJ, Zhao XY, Cohen P, Feldman D (2001) 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 165:1319–1324
Stewart LV, Weigel NL (2005) Role of insulin-like growth factor binding proteins in 1alpha,25-dihydroxyvitamin D(3)-induced growth inhibition of human prostate cancer cells. Prostate 64:9–19
Dougherty KM, Blomme EA, Koh AJ, Henderson JE, Pienta KJ, Rosol TJ, McCauley LK (1999) Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. Cancer Res 59:6015–6022
Tovar Sepulveda VA, Falzon M (2003) Prostate cancer cell type-specific regulation of the human PTHrP gene via a negative VDRE. Mol Cell Endocrinol 204:51–64
Bhatia V, Mula RV, Falzon M (2011) 1,25-Dihydroxyvitamin D(3) regulates PTHrP expression via transcriptional, post-transcriptional and post-translational pathways. Mol Cell Endocrinol 352:32–40
Shen X, Mula RV, Li J, Weigel NL, Falzon M (2007) PTHrP contributes to the anti-Âproliferative and integrin alpha6beta4-regulating effects of 1,25-dihydroxyvitamin D(3). Steroids 72:930–938
Kallay E, Pietschmann P, Toyokuni S, Bajna E, Mazzucco K, Bieglmayer C, Kato S, Cross HS (2001) Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage. Carcinogenesis 22:1429–1435
Fedirko V, Bostick RM, Long Q, Flanders WD, McCullough ML, Sidelnikov E, Daniel CR, Rutherford RE, Shaukat A (2010) Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial. Cancer Epidemiol Biomarkers Prev 19:280–291
Bao BY, Ting HJ, Hsu JW, Lee Y-F (2008) Protective role of 1 alpha, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int J Cancer 122:2699–2706
Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, Brooks JD, Feldman D (2004) Molecular activity of 1,25-dihydroxyvitamin D3 in primary cultures of human prostatic Âepithelial cells revealed by cDNA microarray analysis. J Steroid Biochem Mol Biol 92:131–141
Ting HJ, Yasmin-Karim S, Yan SJ, Hsu JW, Lin TH, Zeng W, Messing J, Sheu TJ, Bao BY, Li WX, Messing E, Lee YF (2012) A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D. Cancer Res 72:958–968
Wang J, Sarkar TR, Zhou M, Sharan S, Ritt DA, Veenstra TD, Morrison DK, Huang AM, Sterneck E (2010) CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage. Proc Natl Acad Sci USA 107:16131–16136
Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE (2000) 1 alpha,25-Âdihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res 87:214–220
Bernardi RJ, Johnson CS, Modzelewski RA, Trump DL (2002) Antiproliferative effects of 1alpha,25-dihydroxyvitamin D(3) and vitamin D analogs on tumor-derived endothelial cells. Endocrinology 143:2508–2514
Chung I, Han G, Seshadri M, Gillard BM, Yu WD, Foster BA, Trump DL, Johnson CS (2009) Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo. Cancer Res 69:967–975
Campbell CL, Savarese DM, Quesenberry PJ, Savarese TM (2001) Expression of multiple angiogenic cytokines in cultured normal human prostate epithelial cells: predominance of vascular endothelial growth factor. Int J Cancer 80:868–874
Cardus A, Panizo S, Encinas M, Dolcet X, Gallego C, Aldea M, Fernandez E, Valdiveilso JM (2009) 1,25-dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter. Atherosclerosis 204:85–89
Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, Mabjeesh NJ (2007) 1alpha,25-Âdihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther 6:1433–1439
Li A, Dubey S, Varney ML, Dave BJ, Singh RK (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170:3369–3376
Bao BY, Yao J, Lee YF (2006) 1α,25-dihydroxyvitamin D3 suppresses interleukin-8-Âmediated prostate cancer cell angiogenesis. Carcinogenesis 27:1883–1893
Sfanos KS, de Marzo AM (2012) Prostate cancer and inflammation: the evidence. Histopathology 60:199–215
Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H (2000) Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 42:73–78
Kirschenbaum A, Klausner AP, Lee R, Unger P, Yao S, Liu XH, Levine AC (2000) Expression of cyclooxygenase-1 and cyclooxygenase-2 in the human prostate. Urology 56:671–676
Lee LM, Pan CC, Cheng CJ, Chi CW, Liu TY (2001) Expression of cyclooxygenase-2 in prostate adenocarcinoma and benign prostatic hyperplasia. Anticancer Res 21:1291–1294
Yoshimura R, Sano H, Masuda C, Kawamura M, Tsubouchi Y, Chargui J, Yoshimura N, Hla T, Wada S (2010) Expression of cyclooxygenase-2 in prostate carcinoma. Cancer 89:589–596
Wang JY, Swami S, Krishnan AV, Feldman D (2012) Combination of calcitriol and dietary soy exhibits enhanced anticancer activity and increased hypercalcemic toxicity in a mouse xenograft model of prostate cancer. Prostate 72:1628–1637
Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D (2005) Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res 65:7917–7925
Marshall DT, Savage SJ, Garrett-Mayer E, Keane TE, Hollis BW, Horst RL, Ambrose LH, Kindy MS, Gattoni-Celli S (2012) Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. J Clin Endocrinol Metab 97:2315–2324
Gross C, Stamey T, Hancock S, Feldman D (1998) Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol). J Urol 159:2035–2039
Beer TM, Lemmon D, Lowe BA, Henner WD (2003) High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer 97:1217–1224
Beer TM, Eilers KM, Garzotto M, Egorin MJ, Lowe BA, Henner WD (2003) Weekly high-Âdose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 21:123–128
Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Redfern CH, Fehrenbacher L, Saleh MN, Waterhouse DM, Carducci MA, Vicario D, Dreicer R, Higano CS, Ahmann FR, Chi KN, Henner WD, Arroyo A, Clow FW, ASCENT Investigators (2007) Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 25:669–674
Seruga B, Tannock IF (2011) Chemotherapy-based treatment for castration-resistant prostate cancer. J Clin Oncol 29:2686–3694
Solomon C, White JH, Kremer R (1999) Mitogen-activated protein kinase inhibits 1,25-Âdihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α. J Clin Invest 103:1729–1735
Zhang Z, Kovalenko P, Ciu M, Desmet M, Clinton SK, Fleet JC (2010) Constitutive activation of the mitogen-activated protein kinase pathway impairs vitamin D signaling in human prostate epithelial cells. J Cell Physiol 224:433–444
Khanim FL, Gommersall LM, Wood VHJ, Smith KL, Montalvo L, O’Neill LP, Xu Y, Peehl DM, Stewart PM, Turner BM, Campbell MJ (2004) Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells. Oncogene 23:6712–6725
Larriba MJ, Bonilla F, Muñoz A (2010) The transcription factors Snail1 and Snail2 repress vitamin D receptor during colon cancer progression. J Steroid Biochem Mol Biol 121:106–109
Yang H, Zhang Y, Zhou Z, Jiang X, Shen A (2011) Snail-1 regulates VDR signaling and inhibits 1,25(OH)-D3 action in osteosarcoma. Eur J Pharmacol 670:341–346
Gross C, Skowronski RJ, Plymate SR, Rhim JS, Peehl DM, Feldman D (1996) Simian virus 40-, but not human papillomavirus-, transformation of prostatic epithelial cells results in loss of growth-inhibition by 1,25-dihydroxyvitamin D3. Int J Oncol 8:41–47
Washington MN, Weigel NL (2010) 1α,25-dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion. Endocrinology 151:1409–1417
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Kim, JS., Roberts, J.M., Weigel, N.L. (2013). Vitamin D and Prostate Cancer. In: Tindall, D. (eds) Prostate Cancer. Protein Reviews, vol 16. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6828-8_15
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DOI: https://doi.org/10.1007/978-1-4614-6828-8_15
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