The role of vitamin D3 in signaling pathways – potential anticancer properties of calcitriol and its analogues
Olga Wiecheć 1Abstract
Vitamin D, for many years after the discovery, primarily was associated with bone metabolic processes. Currently, many studies indicate its beneficial effect in the prevention and treatment of many diseases, including cancer. However, deficiency of vitamin D is associated with greater tendency to get sick and worse prognosis in treatment, especially cancer. Calcitriol, an active form of vitamin D (1.25(OH)2D3) and its analogues have a pleiotropic activity, including anti-cancer properties. Many studies indicate, that the active forms of vitamin D3 may show anti-proliferative effects in cancer cells by inhibiting the cell cycle, inducing differentiation or leading to apoptosis and enhancing autophagy. Also, extremely important are the possibilities of reducing the invasiveness of tumours through the influence on angiogenesis or adhesion and others. Especially, the anti-cancer role of vitamin D3 is suggested in the case of tumors whose cells express VDR receptors. Interestingly, many cancer cells not only express the VDR receptors, but also due to the expression of CYP27B1 and CYP24A hydroxylases, they can regulate metabolism of calcitriol. Many of the studies using vitamin D3 show that calcitriol and its analogues, due to the influence on cancer cells, can play promising roles in anticancer therapies. Consider the broad pleiotropism of the action of active metabolites of vitamin D3 and the development of research in this field, the current work presents the effect of active forms of vitamin D on some signalling pathways and the regulation of selected proteins in various cancers.
References
- 1. Aguilera O., Pena C., Garcia J.M., Larriba M.J., Ordonez-Moran P.,Navarro D., Barbachano A., Lopez de Silanes I., Ballestar E., FragaM.F., Esteller M., Gamallo C., Bonilla F., Gonzalez-Sancho J.M., MunozA.: The Wnt antagonist DICKKOPF-1 gene is induced by 1α,25-dihydroxyvitamin D3 associated to the differentiation of humancolon cancer cells. Carcinogenesis, 2007; 28: 1877–1884
Google Scholar - 2. Anderson M.G., Nakane M., Ruan X., Kroeger P.E., Wu-Wong J.R.:Expression of VDR and CYP24A1 mRNA in human tumors. CancerChemother. Pharmacol., 2006; 57: 234–240
Google Scholar - 3. Annalora A.J., Goodin D.B., Hong W.X., Zhang Q., Johnson E.F., StoutC.D.: Crystal structure of CYP24A1, a mitochondrial cytochrome P450involved in Vitamin D metabolism. J. Mol. Biol., 2010; 396: 441–451
Google Scholar - 4. Artaza J.N., Sirad F., Ferrini M.G., Norris K.C.: 1,25(OH)2vitaminD3 inhibits cell proliferation by promoting cell cycle arrest withoutinducing apoptosis and modifies cell morphology of mesenchymalmultipotent cells. J. Steroid Biochem. Mol. Biol., 2010; 119: 73–83
Google Scholar - 5. Autier P., Gandini S.: Vitamin D supplementation and total mortality:a meta-analysis of randomized controlled trials. Arch. Intern.Med., 2007; 167: 1730–1737
Google Scholar - 6. Avila E., García-Becerra R., Rodríguez-Rasgado J.A., Díaz L., Ordaz-Rosado D., Zügel U., Steinmeyer A., Barrera D., Halhali A., LarreaF., Camacho J.: Calcitriol down-regulates human ether à go-go 1potassium channel expression in cervical cancer cells. AnticancerRes., 2010; 30: 2667–2672
Google Scholar - 7. Banakar M.C., Paramasivan S.K., Chattopadhyay M.B., Datta S., ChakrabortyP., Chatterjee M., Kannan K., Thygarajan E.: 1α, 25-dihydroxyvitaminD3 prevents DNA damage and restores antioxidant enzymesin rat hepatocarcinogenesis induced by diethylnitrosamine and promotedby phenobarbital. World J. Gastroenterol., 2004; 10: 1268–1275
Google Scholar - 8. Bao B.Y., Ting H.J., Hsu J.W., Lee Y.F.: Protective role of 1α, 25-dihydroxyvitaminD3 against oxidative stress in nonmalignant humanprostate epithelial cells. Int. J. Cancer, 2008; 122: 2699–2706
Google Scholar - 9. Bao B.Y., Yao J., Lee Y.F.: 1α, 25-dihydroxyvitamin D3 suppressesinterleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis,2006; 27: 1883–1893
Google Scholar - 10. Bao Y., Ng K., Wolpin B.M., Michaud D.S., Giovannucci E., FuchsC.S.: Predicted vitamin D status and pancreatic cancer risk in twoprospective cohort studies. Br. J. Cancer, 2010; 102: 1422–1427
Google Scholar - 11. Bareis P., Bises G., Bischof M.G., Cross H.S., Peterlik M.: 25-Hydroxy-vitamin D metabolism in human colon cancer cells during tumorprogression. Biochem. Biophys. Res. Commun., 2001; 285: 1012–1017
Google Scholar - 12. Berlanga-Taylor A.J., Knight J.C.: An integrated approach to defininggenetic and environmental determinants for major clinicaloutcomes involving vitamin D. Mol. Diagn. Ther., 2014; 18: 261–272
Google Scholar - 13. Bertone-Johnson E.R., Chen W.Y., Holick M.F., Hollis B.W., ColditzG.A., Willett W.C., Hankinson S.E.: Plasma 25-hydroxyvitamin D and1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol.Biomarkers Prev., 2005; 14: 1991–1997
Google Scholar - 14. Bessler H., Djaldetti M.: 1α,25-dihydroxyvitamin D3 modulatesthe interaction between immune and colon cancer cells. Biomed.Pharmacother., 2012; 66: 428–432
Google Scholar - 15. Bikle D.D.: Vitamin D metabolism, mechanism of action, andclinical applications. Chem. Biol., 2014; 21: 319–329
Google Scholar - 16. Bikle D.D., Elalieh H., Welsh J., Oh D., Cleaver J., Teichert A.:Protective role of vitamin D signaling in skin cancer formation. J.Steroid Biochem. Mol. Biol., 2013; 136: 271–279
Google Scholar - 17. Brożyna A.A., Jóźwicki W., Janjetovic Z., Slominski A.T.: Expressionof the vitamin D–activating enzyme 1α-hydroxylase (CYP27B1) decreasesduring melanoma progression. Hum. Pathol., 2013; 44: 374–387
Google Scholar - 18. Brożyna A.A., Józwicki W., Jochymski C., Slominski A.T.: Decreasedexpression of CYP27B1 correlates with the increased aggressivenessof ovarian carcinomas. Oncol. Rep., 2015; 33: 599–606
Google Scholar - 19. Brożyna A.A., Jóźwicki W., Slominski A.T.: Decreased VDR expressionin cutaneous melanomas as marker of tumor progression: Newdata and analyses. Anticancer Res., 2014; 34: 2735–2744
Google Scholar - 20. Burns E.M., Elmets C.A., Yusuf N.: Vitamin D and skin cancer.Photochem. Photobiol., 2015; 91: 201–209
Google Scholar - 21. Buttigliero C., Monagheddu C., Petroni P., Saini A., Dogliotti L.,Ciccone G., Berruti A.: Prognostic role of vitamin D status and efficacyof vitamin D supplementation in cancer patients: A systematicreview. Oncologist, 2011; 16: 1215–1227
Google Scholar - 22. Caligo M.A., Cipollini G., Petrini M., Valentini P., Bevilacqua G.:Down regulation of NM23.H1, NM23.H2 and c-myc genes duringdifferentiation induced by 1,25 dihydroxyvitamin D3. Leuk. Res.,1996; 20: 161–167
Google Scholar - 23. Cazares-Ordonez V., Gonzalez-Duarte R.J., Diaz L., Ishizawa M.,Uno S., Ortiz V., Ordonez-Sanchez M.L., Makishima M., Larrea F.,Avila E.: A cis-acting element in the promoter of human ether a go–go 1 potassium channel gene mediates repression by calcitriol inhuman cervical cancer cells. Biochem. Cell Biol., 2015; 93: 94–101
Google Scholar - 24. Chen T.C., Holick M.F.: Vitamin D and prostate cancer preventionand treatment. Trends Endocrinol. Metab., 2003; 14: 423–430
Google Scholar - 25. Chen Y., Zhang J., Ge X., Du J., Deb D.K., Li Y.C.: Vitamin D receptorinhibits nuclear factor κB activation by interacting with IκBkinase β protein. J. Biol. Chem., 2013; 288: 19450–19458
Google Scholar - 26. Christakos S., Dhawan P., Verstuyf A., Verlinden L., CarmelietG.: Vitamin D: Metabolism, molecular mechanism of action, andpleiotropic effects. Physiol. Rev., 2016; 96: 365–408
Google Scholar - 27. Colston K., Colston M.J., Feldman D.: 1,25-dihydroxevitamin D3and malignant melanoma: the presence of receptors and inhibitionof cell growth in culture. Endocrinology, 1981; 108: 1083–1086
Google Scholar - 28. Colston K.W., James S.Y., Ofori-Kuragu E.A., Binderup L., GrantA.G.: Vitamin D receptors and anti-proliferative effects of vitaminD derivatives in human pancreatic carcinoma cells in vivo and invitro. Br. J. Cancer, 1997; 76: 1017–1020
Google Scholar - 29. Deeb K.K., Trump D.L., Johnson C.S.: Vitamin D signalling pathwaysin cancer: Potential for anticancer therapeutics. Nat. Rev.Cancer, 2007; 7: 684–700
Google Scholar - 30. Díaz L., Díaz-Muñoz M., García-Gaytán A.C., Méndez I.: Mechanisticeffects of calcitriol in cancer biology. Nutrients, 2015; 7: 5020–5050
Google Scholar - 31. Didonato J.A., Mercurio F., Karin M.: NF-kB and the link betweeninflammation and cancer. Immunol. Rev., 2012; 246: 379–400
Google Scholar - 32. Doroudi M., Schwartz Z., Boyan B.D.: Phospholipase A2 activatingprotein is required for 1α,25-dihydroxyvitamin D3 dependentrapid activation of protein kinase C via Pdia3. J. Steroid Biochem.Mol. Biol., 2012; 132: 48–56
Google Scholar - 33. Ferrer-Mayorga G., Larriba M.J., Crespo P., Muñoz A.: Mechanismsof action of vitamin D in colon cancer. J. Steroid Biochem. Mol.Biol., 2019; 185: 1–6
Google Scholar - 34. Field S., Elliott F., Randerson-Moor J., Kukalizch K., Barrett J.H.,Bishop D.T., Newton-Bishop J.A.: Do vitamin A serum levels moderateoutcome or the protective effect of vitamin D on outcome frommalignant melanoma? Clin. Nutr., 2013; 32: 1012–1016
Google Scholar - 35. Fleet J.C.: Molecular actions of vitamin D contributing to cancerprevention. Mol. Aspects Med., 2008; 29: 388-396
Google Scholar - 36. Fleet J.C., DeSmet M., Johnson R., Li Y.: Vitamin D and cancer:a review of molecular mechanisms. Biochem. J., 2012; 441: 61–76
Google Scholar - 37. García-Becerra R., Díaz L., Camacho J., Barrera D., Ordaz-RosadoD., Morales A., Ortiz C.S., Avila E., Bargallo E., Arrecillas M., HalhaliA., Larrea F.: Calcitriol inhibits ether-à go-go potassium channelexpression and cell proliferation in human breast cancer cells. Exp.Cell Res., 2010; 316: 433–442
Google Scholar - 38. García-Quiroz J., García-Becerra R., Santos-Martínez N., BarreraD., Ordaz-Rosado D., Avila E., Halhali A., Villanueva O., Ibarra-SánchezM.J., Esparza-López J., Gamboa-Domínguez A., Camacho J., Larrea F.,Díaz L.: In vivo dual targeting of the oncogenic ether-à-go-go-1 potassiumchannel by calcitriol and astemizole results in enhanced antineoplasticeffects in breast tumors. BMC Cancer, 2014; 14: 745–754
Google Scholar - 39. Garland C.F., Gorham E.D., Mohr S.B., Grant W.B., GiovannucciE.L., Lipkin M., Newmark H., Holick M.F., Garland F.C.: Vitamin D andprevention of breast cancer: Pooled analysis. J. Steroid Biochem. Mol.Biol., 2007; 103: 708–711
Google Scholar - 40. Goodwin P.J., Ennis M., Pritchard K.I., Koo J., Hood N.: Prognosticeffects of 25-hydroxyvitamin D levels in early breast cancer. J. Clin.Oncol., 2009; 27: 3757–3763
Google Scholar - 41. Gorham E.D., Garland C.F., Garland F.C., Grant W.B., Mohr S.B.,Lipkin M., Newmark H.L., Giovannucci E., Wei M., Holick M.F.: VitaminD and prevention of colorectal cancer. J. Steroid Biochem. Mol.Biol., 2005; 97: 179–194
Google Scholar - 42. Guzey M., Kitada S., Reed J.C.: Apoptosis induction by 1α,25-dihydroxyvitamin D3 in prostate cancer. Mol. Cancer Ther., 2002;1: 667–677
Google Scholar - 43. Hager G., Kornfehl J., Knerer B., Weigel G., Formanek M.: Molecularanalysis of p21 promoter activity isolated from squamous carcinomacell lines of the head and neck under the influence of 1,25(OH)2vitamin D3 and its analogs. Acta Otolaryngol., 2004; 124: 90–96
Google Scholar - 44. Haussler M.R., Whitfield G.K., Haussler C.A., Hsieh J.C., ThompsonP.D., Selznick S.H., Dominguez C.E., Jurutka P.W.: The nuclearvitamin D receptor: Biological and molecular regulatory propertiesrevealed. J. Bone Miner. Res., 1998; 13: 325–349
Google Scholar - 45. Henry H.L.: Regulation of vitamin D metabolism. Best Pract. Res.Clin. Endocrinol. Metab., 2011; 25: 531–541
Google Scholar - 46. Hmama Z., Nandan D., Sly L., Knutson K.L., Herrera-Velit P.,Reiner N.E.: 1α,25-Dihydroxyvitamin D3-induced myeloid cell differentiationis regulated by a vitamin D receptor-phosphatidylinositol3-kinase signaling complex. J. Exp. Med., 1999; 190: 1583–1594
Google Scholar - 47. Holick M.F.: Vitamin D: A millenium perspective. J. Cell. Biochem.,2003; 88: 296–307
Google Scholar - 48. Holick M.F.: Vitamin D deficiency. N. Engl. J. Med., 2007; 357: 266–281
Google Scholar - 49. Hossein-Nezhad A., Holick M.F.: Vitamin D for health: A globalperspective. Mayo Clin. Proc., 2013; 88: 720–755
Google Scholar - 50. Huynh H., Pollak M., Zhang J.C.: Regulation of insulin-like growthfactor (IGF) II and IGF binding protein 3 autocrine loop in humanPC-3 prostate cancer cells by vitamin D metabolite 1,25(OH)2D3 andits analog EB1089. Int. J. Oncol., 1998; 13: 137–143
Google Scholar - 51. Hybertson B.M., Gao B., Bose S.K., McCord J.M.: Oxidative stressin health and disease: The therapeutic potential of Nrf2 activation.Mol. Aspects Med., 2011; 32: 234–246
Google Scholar - 52. Ingraham B.A., Bragdon B., Nohe A.: Molecular basis of the potentialof vitamin D to prevent cancer. Curr. Med. Res. Opin., 2008; 24: 139–149
Google Scholar - 53. James S.Y., Mackay A.G., Colston K.W.: Effects of 1,25 dihydroxyvitaminD3 and its analogues on induction of apoptosis in breastcancer cells. J. Steroid Biochem. Mol. Biol., 1996; 58: 395–401
Google Scholar - 54. Janjetovic Z., Brozyna A.A., Tuckey R.C., Kim T.K., Nguyen M.N.,Jozwicki W., Pfeffer S.R., Pfeffer L.M., Slominski A.T.: High basal NF-κB activity in nonpigmented melanoma cells is associated with anenhanced sensitivity to vitamin D3 derivatives. Br. J. Cancer, 2011;105: 1874–1884
Google Scholar - 55. Jensen S.S., Madsen M.W., Lukas J., Binderup L., Bartek J.: Inhibitoryeffects of 1α,25-dihydroxyvitamin D3 on the G1-S phase-controllingmachinery. Mol. Endocrinol., 2001; 15: 1370–1380
Google Scholar - 56. Jiang F., Bao J., Li P., Nicosia S.V., Bai W.: Induction of ovarian cancercell apoptosis by 1,25-dihydroxyvitamin D3 through the down–regulation of telomerase. J. Biol. Chem., 2004; 279: 53213–53221
Google Scholar - 57. Jóźwicki W., Brożyna A., Siekiera J., Slominski A.: Expression ofvitamin D receptor (VDR) positively correlates with survival of urothelialbladder cancer patients. Int. J. Mol. Sci., 2015; 16: 24369–24386
Google Scholar - 58. Kizildag S., Ates H., Kizildag S.: Treatment of K562 cells with1,25-dihydroxyvitamin D3 induces distinct alterations in the expressionof apoptosis-related genes BCL2, BAX, BCLXL, and p21. Ann.Hematol., 2010; 89: 1–7
Google Scholar - 59. Köstner K., Denzer N., Müller C.S., Klein R., Tilgen W., ReichrathJ.: The relevance of vitamin D receptor (VDR) gene polymorphismsfor cancer: A review of the literature. Anticancer Res., 2009;29: 3511–3536
Google Scholar - 60. Kovalenko P.L., Zhang Z., Cui M., Clinton S.K., Fleet J.C.: 1,25dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostateepithelial cell line, RWPE1. BMC Genomics, 2010; 11: 26–40
Google Scholar - 61. Krishnan A. V., Feldman D.: Molecular pathways mediating the anti–inflammatory effects of calcitriol: Implications for prostate cancer chemopreventionand treatment. Endocr. Relat. Cancer, 2010; 17: R19–R38
Google Scholar - 62. Krishnan A. V., Moreno J., Nonn L., Malloy P., Swami S., PengL., Peehl D.M., Feldman D.: Novel pathways that contribute to theanti-proliferative and chemopreventive activities of calcitriol inprostate cancer. J. Steroid Biochem. Mol. Biol., 2007; 103: 694–702
Google Scholar - 63. Lai Y.H., Fang T.C.: The pleiotropic effect of vitamin D. ISRN Nephrol.,2013; 2013: 898125
Google Scholar - 64. Lambert J.R., Kelly J.A., Shim M., Huffer W.E., Nordeen S.K., BaekS.J., Eling T.E., Lucia M.S.: Prostate derived factor in human prostatecancer cells: Gene induction by vitamin D via a p53-dependentmechanism and inhibition of prostate cancer cell growth. J. Cell.Physiol., 2006; 208: 566–574
Google Scholar - 65. Larriba M.J., González-Sancho J.M., Barbáchano A., Niell N.,Ferrer-Mayorga G., Muñoz A.: Vitamin D is a multilevel repressor ofWnt/β-catenin signaling in cancer cells. Cancers, 2013; 5: 1242–1260
Google Scholar - 66. Larriba M.J., González-Sancho J.M., Bonilla F., Muñoz A.: Interactionof vitamin D with membrane-based signaling pathways. Front.Physiol., 2014; 5: 60–70
Google Scholar - 67. Lehmann B., Meurer M.: Vitamin D metabolism. Dermatol. Ther.,2010; 23: 2–12
Google Scholar - 68. Li P., Li C., Zhao X., Zhang X., Nicosia S. V., Bai W.: p27Kip1 Stabilizationand G1 arrest by 1,25-dihydroxyvitamin D3 in ovarian cancercells mediated through down-regulation of cyclin E/cyclin-dependentkinase 2 and Skp1-cullin-F-box protein/Skp2 ubiquitin ligase.J. Biol. Chem., 2004; 279: 25260–25267
Google Scholar - 69. Li Z., Jia Z., Gao Y., Xie D., Wei D., Cui J., Mishra L., Huang S.,Zhang Y., Xie K.: Activation of vitamin D receptor signaling downregulatesthe expression of nuclear FOXM1 protein and suppressespancreatic cancer cell stemness. Clin. Cancer Res., 2015; 21: 844–853
Google Scholar - 70. Lieberman D.A. Prindiville S., Weiss D.G., Willett W.: Risk factorsfor advanced colonic neoplasia and hyperplastic polyps in asymptomaticindividuals. JAMA, 2003; 290: 2959–2967
Google Scholar - 71. Liu M., Lee M.H., Cohen M., Bommakanti M., Freedman L.P.:Transcriptional activation of the Cdk inhibitor p21 by vitamin D3leads to the induced differentiation of the myelomonocytic cell lineU937. Genes Dev., 1996; 10: 142–153
Google Scholar - 72. Liu Y., Wang X., Sun X., Lu S., Liu S.: Vitamin intake and pancreaticcancer risk reduction: A meta-analysis of observational studies.Medicine, 2018; 97: e0114–e0121
Google Scholar - 73. Ma Y., Hu Q., Luo W., Pratt R.N., Glenn S.T., Liu S., Trump D.L.,Johnson C.S.: 1α,25(OH)2D3 differentially regulates miRNA expressionin human bladder cancer cells. J. Steroid Biochem. Mol. Biol.,2015; 148: 166–171
Google Scholar - 74. Mantell D.J., Owens P.E., Bundred N.J., Mawer E.B., Canfield A.E.:1α,25-Dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo.Circ. Res., 2000; 87: 214–220
Google Scholar - 75. Moreno J., Krishnan A. V., Swami S., Nonn L., Peehl D.M., FeldmanD.: Regulation of prostaglandin metabolism by calcitriol attenuatesgrowth stimulation in prostate cancer cells. Cancer Res.,2005; 65: 7917–7925
Google Scholar - 76. Muto A., Kizaki M., Yamato K., Kawai Y., Kamata-Matsushita M.,Ueno H., Ohguchi M., Nishihara T., Koeffler H.P., Ikeda Y.: 1,25-DihydroxyvitaminD3 induces differentiation of a retinoic acid-resistantacute promyelocytic leukemia cell line (UF-1) associatedwith expression of p21 WAF1/CIP1 and p27 KIP1. Blood, 1999; 93: 2225–2233
Google Scholar - 77. Nakagawa K., Kawaura A., Kato S., Takeda E., Okano T.: 1α,25-Dihydroxyvitamin D3 is a preventive factor in the metastasis of lungcancer. Carcinogenesis, 2005; 26: 429–440
Google Scholar - 78. Noyola-Martínez N., Díaz L., Avila E., Halhali A., Larrea F., BarreraD.: Calcitriol downregulates TNF-α and IL-6 expression in culturedplacental cells from preeclamptic women. Cytokine, 2013;61: 245–250
Google Scholar - 79. Pálmer H.G., González-Sancho J.M., Espada J., Berciano M.T.,Puig I., Baulida J., Quintanilla M., Cano A., de Herreros A.G., LafargaM., Muñoz A.: Vitamin D3 promotes the differentiation of coloncarcinoma cells by the induction of E-cadherin and the inhibitionof β-catenin signaling. J. Cell Biol., 2001; 154: 369–387
Google Scholar - 80. Pálmer H.G., Larriba M.J., García J.M., Ordóñez-Morán P., PeñaC., Peiró S., Puig I., Rodríguez R., De La Fuente R., Bernad A., PollánM., Bonilla F., Gamallo C., García De Herreros A., Muñoz A.: The transcriptionfactor SNAIL represses vitamin D receptor expression andresponsiveness in human colon cancer. Nat. Med., 2004; 10: 917–919
Google Scholar - 81. Pálmer H.G., Sánchez-carbayo M., Ordóñez-morán P., LarribaM.J., Cordon-Cardo C., Munoz A.: Genetic signatures of differentiationinduced by 1α,25-dihydroxyvitamin D3 in human colon cancercells. Cancer Res., 2003; 63: 7799–7806
Google Scholar - 82. Peehl D.M., Shinghal R., Nonn L., Seto E., Krishnan A. V., BrooksJ.D., Feldman D.: Molecular activity of 1,25-dihydroxyvitaminD3 in primary cultures of human prostatic epithelial cells revealedby cDNA microarray analysis. J. Steroid Biochem. Mol. Biol., 2004;92: 131–141
Google Scholar - 83. Prosser D.E., Jones G.: Enzymes involved in the activation andinactivation of vitamin D. Trends Biochem. Sci., 2004; 29: 664–673
Google Scholar - 84. Prüfer K., Racz A., Lin G.C., Barsony J.: Dimerization with retinoidX receptors promotes nuclear localization and subnuclear targetingof vitamin D receptors. J. Biol. Chem., 2000; 275: 41114–41123
Google Scholar - 85. Reichrath J., Lehmann B., Carlberg C., Varani J., Zouboulis C.C.:Vitamins as hormones. Horm. Metab. Res., 2007; 39: 71–84
Google Scholar - 86. Rohan J.N., Weigel N.L.: 1α,25-Dihydroxyvitamin D3 reducesc-myc expression, inhibiting proliferation and causing G1 accumulationin C4-2 prostate cancer cells. Endocrinology, 2009; 150:2046–2054
Google Scholar - 87. Saramäki A., Banwell C.M., Campbell M.J., Carlberg C.: Regulationof the human p21waf1/cip1 gene promoter via multiple binding sites forp53 and the vitamin D3 receptor. Nucleic Acids Res., 2006; 34: 543–554
Google Scholar - 88. Sawada N., Inoue M., Iwasaki M., Yamaji T., Shimazu T., SasazukiS., Tsugane S.: Plasma 25-hydroxy vitamin D and subsequent prostatecancer risk in a nested case-control study in Japan: The JPHCstudy. Eur. J. Clin. Nutr., 2017; 71: 132–136
Google Scholar - 89. Schwartz G.G., Eads D., Rao A., Cramer S.D., Willingham M.C.,Chen T.C., Jamieson D.P., Wang L., Burnstein K.L., Holick M.F., KoumenisC.: Pancreatic cancer cells express 25-hydroxyvitamin D-1α-hydroxylase and their proliferation is inhibited by the prohormone25-hydroxyvitamin D3. Carcinogenesis, 2004; 25: 1015–1026
Google Scholar - 90. Schwartz G.G., Whitlatch L.W., Chen T.C., Lokeshwar B.L., Holick M.F.:Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitaminD3. Cancer Epidemiol. Biomarkers Prev., 1998; 7: 391–395
Google Scholar - 91. Scott M.G., Gronowski A.M., Reid I.R., Holick M.F., Thadhani R.,Phinney K.: Vitamin D: The more we know, the less we know. Clin.Chem., 2015; 61: 462–465
Google Scholar - 92. Shabahang M., Buras R.R., Davoodi F., Schumaker L.M., NautaR.J., Evans S.R.: 1,25-Dihydroxyvitamin D3 receptor as a marker ofhuman colon carcinoma cell line differentiation and growth inhibition.Cancer Res., 1993; 53: 3712–3718
Google Scholar - 93. Sherr C.J., Roberts J.M.: Inhibitors of mammalian G1 cyclin-dependentkinases. Genes Dev., 1995; 9: 1149–1163
Google Scholar - 94. Simboli-Campbell M., Narvaez C.J., Tenniswood M., Welsh J.:1,25-Dihydroxyvitamin D3 induces morphological and biochemicalmarkers of apoptosis in MCF-7 breast cancer cells. J. Steroid Biochem.Mol. Biol., 1996; 58: 367–376
Google Scholar - 95. Skowronski R.J., Peehl D.M., Feldman D.: Vitamin D and prostatecancer: 1,25 dihydroxyvitamin D3 receptors and actions in humanprostate cancer cell lines. Endocrinology, 1993; 132: 1952–1960
Google Scholar - 96. Slominski A.T., Brozyna A., Jozwicki W., Tuckey R.C.: Vitamin Das an adjuvant in melanoma therapy. Melanoma Manag., 2015; 2: 1–4
Google Scholar - 97. Slominski A.T., Brożyna A.A., Zmijewski M.A., Jóźwicki W., JettenA.M., Mason R.S., Tuckey R.C., Elmets C.A.: Vitamin D signaling andmelanoma: role of vitamin D and its receptors in melanoma progressionand management. Lab. Investig., 2017; 97: 706–724
Google Scholar - 98. Slominski A.T., Kim T.K., Hobrath J. V., Oak A.S., Tang E.K., TieuE.W., Li W., Tuckey R.C., Jetten A.M.: Endogenously produced nonclassicalvitamin D hydroxy-metabolites act as “biased” agonists onVDR and inverse agonists on RORα and RORγ. J. Steroid Biochem.Mol. Biol., 2017; 173: 42–56
Google Scholar - 99. Slominski A.T., Kim T.K., Li W., Postlethwaite A., Tieu E.W., TangE.K., Tuckey R.C.: Detection of novel CYP11A1-derived secosteroidsin the human epidermis and serum and pig adrenal gland. Sci. Rep.,2015; 5: 14875–14886
Google Scholar - 100. Slominski A.T., Kim T.K., Shehabi H.Z., Semak I., Tang E.K.,Nguyen M.N., Benson H.A., Korik E., Janjetovic Z., Chen J., Yates C.R.,Postlethwaite A., Li W., Tuckey R.C.: In vivo evidence for a novel pathwayof vitamin D3 metabolism initiated by P450scc and modified byCYP27B1. FASEB J., 2012; 26: 3901–3915
Google Scholar - 101. Slominski A.T., Kim T.K., Takeda Y., Janjetovic Z., Broz˙yna A.A.,Skobowiat C., Wang J., Postlethwaite A., Li W., Tuckey R.C., JettenA.M.: RORα and ROR γ are expressed in human skin and serve as receptorsfor endogenously produced noncalcemic 20-hydroxy- and20,23-dihydroxyvitamin D. FASEB J., 2014; 28: 2775–2789
Google Scholar - 102. Slominski A.T., Li W., Kim T.K., Semak I., Wang J., Zjawiony J.K.,Tuckey R.C.: Novel activities of CYP11A1 and their potential physiologicalsignificance. J. Steroid Biochem. Mol. Biol., 2015; 151: 25–37
Google Scholar - 103. So J.Y., Smolarek A.K., Salerno D.M., Maehr H., Uskokovic M.,Liu F., Suh N.: Targeting CD44-STAT3 signaling by gemini vitaminD analog leads to inhibition of invasion in basal-like breast cancer.PLoS One, 2013; 8: e54020–e54029
Google Scholar - 104. Sone T., Kerner S., Pike J.W.: Vitamin D receptor interactionwith specific DNA. Association as a 1,25-dihydroxyvitamin D3-modulatedheterodimer. J. Biol. Chem., 1991; 266: 23296–23305
Google Scholar - 105. Stolzenberg-Solomon R.Z., Vieth R., Azad A., Pietinen P., TaylorP.R., Virtamo J., Albanes D.: A prospective nested case-controlstudy of vitamin D status and pancreatic cancer risk in male smokers.Cancer Res., 2006; 66: 10213–10219
Google Scholar - 106. Szyszka P., Zmijewski M.A., Slominski A.T.: New vitamin D analogsas potential therapeutics in melanoma. Expert Rev. AnticancerTher., 2012; 12: 585–599
Google Scholar - 107. Tang E.K., Chen J., Janjetovic Z., Tieu E.W., Slominski A.T., LiW., Tuckey R.C.: Hydroxylation of CYP11A1-derived products of vitaminD3 metabolism by human and Mouse CYP27B1. Drug Metab.Dispos., 2013; 41: 1112–1124
Google Scholar - 108. Tavera-Mendoza L., Wang T.T., Lallemant B., Zhang R., Nagai Y.,Bourdeau V., Ramirez-Calderon M., Desbarats J., Mader S., White J.H.:Convergence of vitamin D and retinoic acid signalling at a commonhormone response element. EMBO Rep., 2006; 7: 180–185
Google Scholar - 109. Tieu E.W., Li W., Chen J., Kim T.K., Ma D., Slominski A.T., TuckeyR.C.: Metabolism of 20-hydroxyvitamin D3 and 20,23-dihydroxyvitaminD3 by rat and human CYP24A1. J. Steroid Biochem. Mol. Biol.,2015; 149: 153–165
Google Scholar - 110. Toner C.D., Davis C.D., Milner J.A.: The vitamin D and cancerconundrum: Aiming at a moving target. J. Am. Diet. Assoc., 2010;110: 1492–1500
Google Scholar - 111. Tong W.M., Hofer H., Ellinger A., Peterlik M., Cross H.S.: Mechanismof antimitogenic action of vitamin D in human colon carcinomacells: relevance for suppression of epidermal growth factor-stimulatedcell growth. Oncol. Res., 1999; 11: 77–84
Google Scholar - 112. Townsend K., Banwell C.M., Guy M., Colston K.W., Mansi J.L.,Stewart P.M., Campbell M.J., Hewison M.: Autocrine metabolism ofvitamin D in normal and malignant breast tissue. Clin. Cancer Res.,2005; 11: 3579–3586
Google Scholar - 113. Wacker M., Holick M.F.: Sunlight and vitamin D. A global perspectivefor health. Dermatoendocrinol., 2013; 5: 51–108
Google Scholar - 114. Wagner N., Wagner K.D., Schley G., Badiali L., Theres H., ScholzH.: 1,25-Dihydroxyvitamin D3-induced apoptosis of retinoblastomacells is associated with reciprocal changes of Bcl-2 and bax. Exp.Eye Res., 2003; 77: 1–9
Google Scholar - 115. Wang Q.M., Jones J.B., Studzinski G.P.: Cyclin-dependent kinaseinhibitor p27 as a mediator of the G1-S phase block induced by 1,25-dihydroxyvitaminD3 in HL60 cells. Cancer Res., 1996; 56: 264–267
Google Scholar - 116. Wasiewicz T., Szyszka P., Cichorek M., Janjetovic Z., Tuckey R.,Slominski A., Zmijewski M.: Antitumor effects of vitamin D analogson hamster and mouse melanoma cell lines in relation to melaninpigmentation. Int. J. Mol. Sci., 2015; 16: 6645–6667
Google Scholar - 117. Wierzbicka J., Piotrowska A., Żmijewski M.A.: The renaissanceof vitamin D. Acta Biochim. Pol., 2014; 61: 679–686
Google Scholar - 118. Yamada O., Ozaki K., Nakatake M., Akiyama M., Kawauchi K.,Matsuoka R.: Multistep regulation of telomerase during differentiationof HL60 cells. J. Leukoc. Biol., 2008; 83: 1240–1248
Google Scholar - 119. Ylikomi T., Laaksi I., Lou Y.R., Martikainen P., Miettinen S., PennanenP., Purmonen S., Syvälä H., Vienonen A., Tuohimaam P.: Antiproliferativeaction of vitamin D. Vitam. Horm., 2002; 64: 357–406
Google Scholar - 120. Zhang X., Nicosia S.V., Bai W.: Vitamin D receptor is a noveldrug target for ovarian cancer treatment. Curr. Cancer Drug Targets,2006; 6: 229–244
Google Scholar