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Vitamin D and Prostate Cancer

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Prostate Cancer

Part of the book series: Protein Reviews ((PRON,volume 16))

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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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References

  1. Christakos S, DeLuca HF (2011) Vitamin D: is there a role in extraskeletal health? Endocrinology 152:2930–2936

    PubMed  CAS  Google Scholar 

  2. 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

    CAS  Google Scholar 

  3. 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

    CAS  Google Scholar 

  4. 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

    PubMed  CAS  Google Scholar 

  5. Christakos S, Ajibade DV, Dhawan P, Fechner AJ, Mady LJ (2010) Vitamin D: metabolism. Endocrinol Metab Clin North Am 39:243–253

    PubMed  CAS  Google Scholar 

  6. Jones G (2008) Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 88:582S–586S

    PubMed  CAS  Google Scholar 

  7. 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

    PubMed  CAS  Google Scholar 

  8. 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

    PubMed  CAS  Google Scholar 

  9. 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

    CAS  Google Scholar 

  10. 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

    PubMed  CAS  Google Scholar 

  11. 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

    PubMed  CAS  Google Scholar 

  12. Chen TC, Wang L, Whitlatch LW, Flanagan JN, Holick MF (2003) Prostatic 25-­hydroxyvitamin D-1α-hydroxylase and its implication in prostate cancer. J Cell Biochem 88:315–322

    PubMed  CAS  Google Scholar 

  13. 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

    PubMed  CAS  Google Scholar 

  14. 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-­hydroxyvitamin D(3) 1, alpha-hydroxylase (CYP27B1) in human malignant glioma. Clin Cancer Res 7:868–875

    PubMed  CAS  Google Scholar 

  15. 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

    PubMed  CAS  Google Scholar 

  16. 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

    PubMed  CAS  Google Scholar 

  17. 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

    PubMed  CAS  Google Scholar 

  18. 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

    PubMed  CAS  Google Scholar 

  19. 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

    PubMed  CAS  Google Scholar 

  20. 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

    PubMed  CAS  Google Scholar 

  21. 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

    PubMed  CAS  Google Scholar 

  22. 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

    PubMed  CAS  Google Scholar 

  23. 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

    PubMed  CAS  Google Scholar 

  24. Holick MF, Matsuoka LY, Wortsman J (1989) Age, vitamin D, and solar ultraviolet. Lancet 2:1104–1105

    PubMed  CAS  Google Scholar 

  25. Giovannucci E (2008) Vitamin D status and cancer incidence and mortality. Adv Exp Med Biol 624:31–42

    PubMed  CAS  Google Scholar 

  26. 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

    PubMed  Google Scholar 

  27. 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

    Google Scholar 

  28. Schwartz GG, Hulka BS (1990) Is vitamin D deficiency a risk factor for prostate cancer? (hypothesis). Anticancer Res 10:1307–1312

    PubMed  CAS  Google Scholar 

  29. 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

    PubMed  CAS  Google Scholar 

  30. Loke TW, Sevfi D, Khadra M (2011) Prostate cancer incidence in Australia correlates inversely with solar radiation. BJU Int 108:66–70

    PubMed  Google Scholar 

  31. 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

    PubMed  CAS  Google Scholar 

  32. 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

    PubMed  CAS  Google Scholar 

  33. 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

    PubMed  CAS  Google Scholar 

  34. 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

    PubMed  CAS  Google Scholar 

  35. 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

    PubMed  CAS  Google Scholar 

  36. 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

    PubMed  CAS  Google Scholar 

  37. 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

    PubMed  CAS  Google Scholar 

  38. 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

    PubMed  CAS  Google Scholar 

  39. 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

    PubMed  CAS  Google Scholar 

  40. 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

    PubMed  CAS  Google Scholar 

  41. 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

    PubMed  CAS  Google Scholar 

  42. 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

    CAS  Google Scholar 

  43. 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

    PubMed  CAS  Google Scholar 

  44. 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

    PubMed  CAS  Google Scholar 

  45. 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

    PubMed  CAS  Google Scholar 

  46. 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

    PubMed  CAS  Google Scholar 

  47. 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

    PubMed  CAS  Google Scholar 

  48. 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

    PubMed  CAS  Google Scholar 

  49. 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

    PubMed  CAS  Google Scholar 

  50. 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

    PubMed  CAS  Google Scholar 

  51. 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

    PubMed  CAS  Google Scholar 

  52. 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

    PubMed  CAS  Google Scholar 

  53. 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

    PubMed  CAS  Google Scholar 

  54. 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

    PubMed  Google Scholar 

  55. 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

    PubMed  CAS  Google Scholar 

  56. 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

    PubMed  CAS  Google Scholar 

  57. 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

    PubMed  CAS  Google Scholar 

  58. 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

    PubMed  Google Scholar 

  59. 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

    PubMed  CAS  Google Scholar 

  60. 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

    PubMed  CAS  Google Scholar 

  61. 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

    PubMed  CAS  Google Scholar 

  62. 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

    PubMed  CAS  Google Scholar 

  63. 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

    PubMed  CAS  Google Scholar 

  64. 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

    PubMed  CAS  Google Scholar 

  65. 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

    PubMed  CAS  Google Scholar 

  66. 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-­governed feed-forward loop that regulates p21(waf1/cip1) expression and function in non-­malignant prostate cells. Nucleic Acids Res 39:2045–2056

    PubMed  CAS  Google Scholar 

  67. 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-­transformed prostate epithelial cell line, RWPE1. BMC Genomics 11:26

    PubMed  Google Scholar 

  68. 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

    PubMed  CAS  Google Scholar 

  69. 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

    PubMed  CAS  Google Scholar 

  70. Bartek J, Lukas J (2001) Pathways governing G1/S transition and their response to DNA damage. FEBS Lett 490:117–122

    PubMed  CAS  Google Scholar 

  71. Dang CV (2012) MYC on the path to cancer. Cell 149:22–35

    PubMed  CAS  Google Scholar 

  72. 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

    PubMed  CAS  Google Scholar 

  73. 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

    PubMed  CAS  Google Scholar 

  74. 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

    PubMed  CAS  Google Scholar 

  75. 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

    PubMed  Google Scholar 

  76. Flores O, Burnstein KL (2010) GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells. Endocrinology 151:4654–4664

    PubMed  CAS  Google Scholar 

  77. 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

    PubMed  CAS  Google Scholar 

  78. Guzey M, Kitada S, Reed JC (2002) Apoptosis induction by 1α,25-dihydroxyvitamin D3 in prostate cancer. Mol Cancer Ther 1:667–677

    PubMed  CAS  Google Scholar 

  79. 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

    PubMed  CAS  Google Scholar 

  80. 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

    PubMed  CAS  Google Scholar 

  81. 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

    PubMed  Google Scholar 

  82. 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

    PubMed  CAS  Google Scholar 

  83. Dennler S, Goumans MJ, ten Dijke P (2002) Transforming growth factor beta signal ­transduction. J Leukoc Biol 71:731–740

    PubMed  CAS  Google Scholar 

  84. 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

    PubMed  CAS  Google Scholar 

  85. Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano JM, Pollak M, Giovannucci E (2002) Insulin-­like growth factor-1 (IGF-1) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 94:1099–1106

    PubMed  CAS  Google Scholar 

  86. 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

    PubMed  CAS  Google Scholar 

  87. 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

    PubMed  CAS  Google Scholar 

  88. 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

    PubMed  CAS  Google Scholar 

  89. 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

    PubMed  CAS  Google Scholar 

  90. 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

    PubMed  CAS  Google Scholar 

  91. 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

    PubMed  CAS  Google Scholar 

  92. 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

    PubMed  CAS  Google Scholar 

  93. 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

    PubMed  CAS  Google Scholar 

  94. 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

    Google Scholar 

  95. Shen X, Mula RV, Li J, Weigel NL, Falzon M (2007) PTHrP contributes to the anti-­proliferative and integrin alpha6beta4-regulating effects of 1,25-dihydroxyvitamin D(3). Steroids 72:930–938

    PubMed  CAS  Google Scholar 

  96. 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

    PubMed  CAS  Google Scholar 

  97. 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

    PubMed  CAS  Google Scholar 

  98. 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

    PubMed  CAS  Google Scholar 

  99. 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 ­epithelial cells revealed by cDNA microarray analysis. J Steroid Biochem Mol Biol 92:131–141

    PubMed  CAS  Google Scholar 

  100. 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

    PubMed  CAS  Google Scholar 

  101. 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

    PubMed  CAS  Google Scholar 

  102. Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE (2000) 1 alpha,25-­dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res 87:214–220

    PubMed  CAS  Google Scholar 

  103. 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

    PubMed  CAS  Google Scholar 

  104. 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

    PubMed  CAS  Google Scholar 

  105. 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

    Google Scholar 

  106. 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

    PubMed  CAS  Google Scholar 

  107. Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, Mabjeesh NJ (2007) 1alpha,25-­dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther 6:1433–1439

    PubMed  CAS  Google Scholar 

  108. 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

    PubMed  CAS  Google Scholar 

  109. Bao BY, Yao J, Lee YF (2006) 1α,25-dihydroxyvitamin D3 suppresses interleukin-8-­mediated prostate cancer cell angiogenesis. Carcinogenesis 27:1883–1893

    PubMed  CAS  Google Scholar 

  110. Sfanos KS, de Marzo AM (2012) Prostate cancer and inflammation: the evidence. Histopathology 60:199–215

    PubMed  Google Scholar 

  111. Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H (2000) Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 42:73–78

    PubMed  CAS  Google Scholar 

  112. 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

    PubMed  CAS  Google Scholar 

  113. 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

    PubMed  CAS  Google Scholar 

  114. 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

    Google Scholar 

  115. 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

    PubMed  CAS  Google Scholar 

  116. 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

    PubMed  CAS  Google Scholar 

  117. 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

    CAS  Google Scholar 

  118. 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

    PubMed  CAS  Google Scholar 

  119. 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

    PubMed  CAS  Google Scholar 

  120. Beer TM, Eilers KM, Garzotto M, Egorin MJ, Lowe BA, Henner WD (2003) Weekly high-­dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 21:123–128

    CAS  Google Scholar 

  121. 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

    CAS  Google Scholar 

  122. Seruga B, Tannock IF (2011) Chemotherapy-based treatment for castration-resistant prostate cancer. J Clin Oncol 29:2686–3694

    Google Scholar 

  123. Solomon C, White JH, Kremer R (1999) Mitogen-activated protein kinase inhibits 1,25-­dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α. J Clin Invest 103:1729–1735

    PubMed  CAS  Google Scholar 

  124. 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

    PubMed  CAS  Google Scholar 

  125. 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

    PubMed  CAS  Google Scholar 

  126. 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

    PubMed  CAS  Google Scholar 

  127. 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

    PubMed  CAS  Google Scholar 

  128. 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

    PubMed  CAS  Google Scholar 

  129. 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

    PubMed  CAS  Google Scholar 

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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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