Vitamin D in cancer chemoprevention

Figures & data

Figure 1. Synthesis and metabolism of secosteroids Vitamin D₃ and Vitamin D₂. In humans, cholecalciferol (Vitamin D₃) is synthesized from 7-dehydrocholesterol upon sunlight exposure. Vitamin D may also be obtained from dietary sources or supplements as ergocalciferol or Vitamin D₂. Vitamin D₃ binds to Vitamin D-binding protein (DBP) in the bloodstream and then is transported to the liver where it is first converted by the enzyme 25-hydroxylase (CYP2R1) to 25-hydroxyvitamin D [25(OH)D]. This molecule is converted by the renal enzyme 1-α hydroxylase (CYP27B1) to 1,25 dihydroxycholecalciferol (calcitriol), which is the active form of Vitamin D. The rate limiting step in catabolism is the degradation of 25(OH)D₃ and 1,25(OH)₂D₃ to 24,25(OH)D₃ and 1,24,25(OH)₂D₃, respectively, which occurs through 24-hydroxylation by mitochondrial 1,25-dihydroxyvitamin D₃ 24-hydroxylase, (CYP24A1). 24,25(OH)D₃ and 1,24,25(OH)₂D₃ are excreted in this form.

Table 1. Proposed mechanisms underlying chemopreventive effects of Vitamin D.

Effect on	Mechanism	References
Cell proliferation	Increased expression of p18, p21, and p27 CDKs inhibitors	Wang et al. (1996), Hager et al. (2001), Colston et al. (2002), Yang and Burstein (2003), Gedlicka et al. (2006), Flores et al. (2010), and Thorne et al. (2011)
	Cell cycle blocking in G1/S transition	Jensen et al. (2001) and Istfan et al. (2007)
	Decreased human telomerase reverse transcriptase (hTERT)	Ikeda et al. (2003), Fedirko et al. (2009), and Kasiappan et al. (2012)
	Post-translational modifications and functional alterations of FoxO proteins	Kim et al. (2009) and An et al., (2010)
Growth factors gene  expression	Inhibition of stimulating effects of IGF-I on cell growth and increased expression of IGFBP-3	Colston et al. (1998), Huynh et al. (1998), Nickerson and Huynh (1999), Boyle et al. (2001), Sprenger et al. (2001), Yang et al. (2001), Peng et al. (2004), Matilainen et al. (2005), and Teegarden and Donkin (2009)
	Increased expression levels of TGF-β or its secretion	Koli and Keski-Oja (1995), Wu et al. (1998), Yang et al. (2001), Chen et al. (2002), Lin et al. (2002), Bizzarri et al. (2003), Pálmer et al. (2003), Swami et al. (2003), Murthy and Weigel (2004), Peehl et al. (2004), Lambert et al. (20066), and Lee et al. (2006)
Signaling pathways	Blocking of the transcriptional regulation mediated by Wnt/β-catenin signaling pathway (decreasing formation of the transcriptional complex TCF4-β-catenin)	Larriba et al. (2013)
	Reduced expression of target genes for β-catenin	Xu et al. (2010)
	Prevention of β-catenin nuclear localization and transactivation by increasing E-cadherin expression	Pálmer et al. (2001), Shah et al. (2006), and Beildeck et al. (2009)
	Upregulation of the Wnt antagonist Dickkopf-1 (DKK-1) protein expression	Pendás-Franco et al. (2008b)
Cell differentiation	Increase of β-catenin and E-cadherin expression levels	Pendás-Franco et al. (2008a) and Lopes et al. (2012)
	Inhibitory effects on epidermal growth factor receptor (EGFR) expression	Gocek and Studzinski (2009)
	Accumulation and phosphorylation of integrins, paxillin, and focal adhesion kinase and down-regulation of mesechymal N-cadherin and myoepithelial P-cadherin	Pendás-Franco et al. (2007)
	Up-regulation of androgen receptor expression in LNCaP cells and increased secretion of prostate-specific antigen (PSA)	Gocek and Studzinski (2009)
	Increased expression of insulin-like growth factor binding protein-3 (IGFBP-3) → up regulating of p21/Cip1 → inhibition of cell proliferation	Boyle et al. (2001) and Krishnan et al. (2004)
	Up-regulation of CCAAT/enhancer-binding protein beta (C/EBP β), expression a transcriptional activator that regulates genes involved in immune and inflammatory response, and which cooperates with NF-κB in regulation of the secretion of IL-6 in neuroendocrine human prostate cancer cells	Xiao et al. (2004)
	Induction of human myeloid leukemia cells differentiation into functional monocytes via increased expression and/or activation of PKC isoforms, PI3K-AKT pathway, p42-ERK p38-ERK, and c-JNK families of MAPKs	Hughes et al. (2010)
Apoptosis	Down-regulation of the expression of anti-apoptotic and pro-survival proteins such as Bcl-2, Bcl-XL, or increase of the expression of pro-apoptotic proteins such as Bax, Bak, and Bad	Blutt et al. (2000) and Diaz et al. (2000)
	Up regulation of PTEN	Pan et al. (2010)
	Increase in the levels of the pro-apoptotic proteins death-associated protein (DAP-3), Fas-associated death domain (FADD), and caspase-3, -4, -6, and -8	Swami et al. (2003)
	Increased gene expression of pro-apoptotic protein G0–G1 switch 2 (G0S2)	Pálmer et al. (2003)
	Recruiting of Ca(2+)-dependent apoptotic effectors: Ca(2+)-dependent μ-calpain and Ca(2+)/calpain-dependent caspase-12	Sergeev (2012)
Autophagy	Decreased inhibition of Bcl-2 on Beclin 1 to induce autophagy; decrease endoplasmic reticulum Bcl-2 to increase calcium to induce autophagy	Mathiasen et al. (1999) and Hoyer-Hansen et al. (2007)
	Decrease of mammalian Target Of Rapamycin (mTOR) protein level and increase of Beclin-1 expression levels to induce autophagy	Hoyer-Hansen et al. (2007), Wang et al. (2008), and Høyer-Hansen et al. (2010, 2005)
	Decreased p19^INK4D → increased autophagy	Tavera-Mendoza et al. (2006)
	Decreased autophagic activity induced by TNF-α	Stubbs et al. (2010)
	Inhibition of IFN-γ release from macrophages and peripheral blood mononuclear cells. This phenomenon may results in an inhibition of IFN-γ induced activation and potentiation of lysosomal activity of macrophages, recruitment of autophagic proteins, and, ultimately, may lead to a decrease of autophagy	Wu and Sun (2011)
	NF-kB expression (?)	Bao et al. (2010), Krishnan and Feldman (2010), Tse et al. (2010), and Janjetovic et al. (2011)
	Induced expression of thioredoxin reductase 1 (TXNRD1)	Swami et al. (2003), Peehl et al. (2004), Kovalenko et al. (2010)
Antioxidant defense and  DNA repair	Increased production of superoxide dismutase 1 and 2 (SOD1 and SOD2) in prostate epithelial cells (PECs) and in androgen-sensitive prostate cancer cells (LNCaP)	Peehl et al. (2004) and Lambert et al. (2006)
	Increase of glucose-6-phosphate dehydrogenase (G6PDH) expression levels	Zhang et al. (2005), Bao et al. (2008), and Kovalenko et al. (2010)
	Induction of nuclear factor erythroid-derived 2-like 2 (NFE2L2) transcription factor that controls the gene expression of several enzymes of the antioxidants systems such as glutathione peroxidase (GPX) 3, heme oxygenase 1 (HMOX-1), and aldo-keto reductase 1C2(AKR1C2)
Regulation of proteins  involved in DNA repair	Regulation of genes coding for DNA repair enzymes	Krishnan et al. (2004) and Nair-Shalliker et al. (2012)
	Overexpression of the (GADD45 α) gene	Akter et al. (1997) and Jiang et al. (2003a)
	Increased expression levels of P53 and proliferating cell nuclear antigen (PCNA) up-regulation of DNA repair genes, ATM, and RAD50	Swami et al. (2003) and Ting et al. (2012)
	Prevention of cathepsin L-mediated degradation of DNA repair protein 53BP1	Gonzalo (2014)
Prostaglandins synthesis  and metabolism	Negative modulator of PGs synthesis and activity. Inverse correlation between COX-2 and VDR expression in breast cancer and ovarian cancer cells	Moreno et al. (2006) and Krishnan and Feldman (2010)
	Decreased the expression levels of COX-2, EP2, and FP. Increased expression of 15-hydroxyprostaglandin-D dehydrogenase (15-PGDH) a NAD+-dependent enzyme involved in the degradation of PGE2	Moreno et al. (2005), Krishnan and Feldman (2010), Cordes et al. (2012), Thill et al. (2012), and Yuan et al. (2012)
Angiogenesis	Inhibition VEGF expression and new blood vessels and the formation in mice transplanted with MCF7 human breast cancer	Mantell et al. (2000)
	Repression of hypoxia-inducible factor 1 (HIF-1)	Ben Shoshan et al. (2007)
	Suppression in SCC tumor cells of the expression of the proangiogenic factor IL-8 via NF-kB-dependent manner thus leading to the inhibition of endothelial cell migration and tube formation	Bao et al. (2006)
	Upregulation of thrombospondin-1 (THSD1) mRNA levels in SW480-ADH human colon tumor cells	Fernandez-Garcia et al. (2005)
	Increase of the intracellular levels of VDR and that of the pro-apoptotic protein p27 which reduces the expression level of signal molecules for angiogenesis, including angiopoietin-2	Bernardi et al. (2002) and Flynn et al. (2006)
	Cell-cycle arrest in the G0/G1 phase and a decrease of the number of cells in the S phase, due to the induction of p27 and the down-regulation of p21 in tumor-derived endothelial cells	Chung et al. (2006)
	Growth arrest of RWPE1 prostatic epithelial cells following decrease in the expression levels of genes coding for NF-kB, IGF-1; inhibition of the transcription of pro-inflammatory cytokines, including IL-1, IL-6, and IL-17; reduction of VEGF and VEGF receptors mRNA levels including the kinase insert domain receptor (KDR) and neuropilin 1 (NRP1). Induction of anti-angiogenic factors and that of molecules involved in the protection of cell from oxidative stress; induction of the expression of numerous isoforms of semaphorins, including SEMA 3B, 3F, and 6D	Kovalenko et al. (2010)
	Inhibition of COX-2 expression levels	Aparna et al. (2008)
	Repressesion of the WNT antagonist DICKKOPF-4 (DKK4) which promotes invasion and angiogenesis in colorectal cancer cells	Pendás-Franco et al. (2008b)
Immune system	Modulation of the expression which encodes for proteins that are crucial for autophagy and for the antimicrobial activity in cells of the innate immune system	Hewison (2011)
	Induction of the expression of cathelicidin (CAMP) and, to a lessen exent, of defensin β2 (DEFB2/HBD2) in different normal and tumor cell types such as colon cancer, acute myeloid leukemia, keratinocytes, human bone marrow cells-derived macrophages, and bone marrow cell	Gombart et al. (2005)
	Alteration of the interrelationship between immune cells and cancer cells leading to a significant decrease in the pro-inflammatory cytokines TNF-α and IL-6	Bessler and Djaldetti (2012)
	Increased differentiation of blood-derived CD34+ cells into dendritic cells and decreased peripheral blood and intratumoral levels of immunosuppressive CD34+ cells in patients with head and neck cancer	Young and Day (2013)

Figure 2. The chemical structure of Vitamin D analogues endowed with cancer chemo-preventive activity.

Wang QM, Jones JB, Studzinski GP. (1996). Cyclin-dependent kinase inhibitor p27 as a mediator of the G1-S phase block induced by 1,25-dihydroxyvitamin D3 in HL60 cells. Cancer Res 56:264–7

 PubMed Web of Science ®Google Scholar

Hager G, Formanek M, Gedlicka C, et al. (2001). 1,25(OH)2 vitamin D3 induces elevated expression of the cell cycle-regulating genes P21 and P27 in squamous carcinoma cell lines of the head and neck. Acta Otolaryngol 121:103–9

 PubMed Web of Science ®Google Scholar

Colston KW, Hansen CM. (2002). Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer 9:45–59

 PubMed Web of Science ®Google Scholar

Yang ES, Burnstein KL. (2003). Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. J Biol Chem 278:46862–8

 PubMed Web of Science ®Google Scholar

Gedlicka C, Hager G, Weissenböck M, et al. (2006). 1,25(OH)2Vitamin D3 induces elevated expression of the cell cycle inhibitor p18 in a squamous cell carcinoma cell line of the head and neck. J Oral Pathol Med 35:472–8

 PubMed Web of Science ®Google Scholar

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 Web of Science ®Google Scholar

Thorne JL, Maguire O, Doig CL. (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 39:2045–56

 Google Scholar

Jensen SS, Madsen MW, Lukas J, et al. (2001). Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery. Mol Endocrinol 15:1370–80

 PubMed Web of Science ®Google Scholar

Istfan NW, Person KS, Holick MF, Chen TC. (2007). 1Alpha,25-Dihydroxyvitamin D and fish oil synergistically inhibit G1/S-phase transition in prostate cancer cells. J Steroid Biochem Mol Biol 103:726–30

 PubMed Web of Science ®Google Scholar

Ikeda N, Uemura H, Ishiguro H, et al. (2003). Combination treatment with 1alpha,25-dihydroxyvitamin D3 and 9-cis-retinoic acid directly inhibits human telomerase reverse transcriptase transcription in prostate cancer cells. Mol Cancer Ther 2:739–46

 PubMedGoogle Scholar

Fedirko V, Bostick RM, Flanders WD, et al. (2009). Effects of vitamin D and calcium on proliferation and differentiation in normal colon mucosa: A randomized clinical trial. Cancer Epidemiol Biomarkers Prev 18:2933–41

 PubMed Web of Science ®Google Scholar

Kasiappan R, Shen Z, Tse AK, et al. (2012). 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through MicroRNA-498. J Biol Chem 287:41297–309

 PubMedGoogle Scholar

Kim J, Lim SY, Shin A, et al. (2009). Fatty fish and fish omega-3 fatty acid intakes decrease the breast cancer risk: A case-control study. BMC Cancer 9:216

 PubMed Web of Science ®Google Scholar

An BS, Tavera-Mendoza LE, Dimitrov V, et al. (2010). Stimulation of Sirt1-regulated FoxO protein function by the ligand-bound vitamin D receptor. Mol Cell Biol 30:4890–900

 PubMed Web of Science ®Google Scholar

Colston KW, Perks CM, Xie SP, Holly JM. (1998). Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. J Mol Endocrinol 20:157–62

 PubMedGoogle Scholar

Huynh H, Pollak M, Zhang JC. (1998). Regulation of insulin-like growth factor (IGF) II and IGF binding protein 3 autocrine loop in human PC-3 prostate cancer cells by vitamin D metabolite 1,25(OH)2D3 and its analog EB1089. Int J Oncol 13:137–43

 PubMedGoogle Scholar

Nickerson T, Huynh H. (1999). Vitamin D analogue EB1089-induced prostate regression is associated with increased gene expression of insulin-like growth factor binding proteins. J Endocrinol 160:223–9

 PubMedGoogle Scholar

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 165:1319–24

 PubMed Web of Science ®Google Scholar

Sprenger CC, Peterson A, Lance R, et al. (2001). Regulation of proliferation of prostate epithelial cells by 1,25-dihydroxyvitamin D3 is accompanied by an increase in insulin-like growth factor binding protein-3. J Endocrinol 170:609–18

 PubMed Web of Science ®Google Scholar

Yang L, Yang J, Venkateswarlu S, et al. (2001). Autocrine TGFbeta signaling mediates vitamin D3 analog-induced growth inhibition in breast cells. J Cell Physiol 188:383–93

 PubMedGoogle Scholar

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 18:1109–19

 PubMed Web of Science ®Google Scholar

Matilainen M, Malinen M, Saavalainen K, Carlberg C. (2005). Regulation of multiple insulin-like growth factor binding protein genes by 1alpha,25-dihydroxyvitamin D3. Nucleic Acids Res 33:5521–32

 PubMed Web of Science ®Google Scholar

Teegarden D, Donkin SS. (2009). Vitamin D: Emerging new roles in insulin sensitivity. Nutr Res Rev 22:82–92

 PubMed Web of Science ®Google Scholar

Koli K, Keski-Oja J. (1995). 1,25-Dihydroxyvitamin D3 enhances the expression of transforming growth factor beta 1 and its latent form binding protein in cultured breast carcinoma cells. Cancer Res 55:1540–6

 PubMed Web of Science ®Google Scholar

Wu G, Fan RS, Li W, et al. (1998). Regulation of transforming growth factor-beta type II receptor expression in human breast cancer MCF-7 cells by vitamin D3 and its analogues. J Biol Chem 273:7749–56

 PubMedGoogle Scholar

Chen A, Davis BH, Sitrin MD, et al. (2002). Transforming growth factor-beta 1 signaling contributes to Caco-2 cell growth inhibition induced by 1,25(OH)2D3. Am J Physiol Gastrointest Liver Physiol 283:864–74

 PubMed Web of Science ®Google Scholar

Lin R, Nagai Y, Sladek R, et al. (2002). Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol 16:1243–56

 PubMedGoogle Scholar

Bizzarri M, Cucina A, Valente MG, et al. (2003). Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures. J Surg Res 110:332–7

 PubMed Web of Science ®Google Scholar

Pálmer HG, Sánchez-Carbayo M, Ordóñez-Morán P, et al. (2003). Genetic signatures of differentiation induced by 1alpha,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res 63:7799–806

 PubMed Web of Science ®Google Scholar

Swami S, Raghavachari N, Muller UR, et al. (2003). Vitamin D growth inhibition of breast cancer cells: Gene expression patterns assessed by cDNA microarray. Breast Cancer Res Treat 80:49–62

 PubMed Web of Science ®Google Scholar

Murthy S, Weigel NL. (2004). 1Alpha,25-dihydroxyvitamin D3 induced growth inhibition of PC-3 prostate cancer cells requires an active transforming growth factor beta signaling pathway. Prostate 59:282–91

 PubMedGoogle Scholar

Peehl DM, Shinghal R, Nonn L, et al. (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 92:131–41

 PubMed Web of Science ®Google Scholar

Lambert JR, Kelly JA, Shim M, et al. (2006). Prostate derived factor in human prostate cancer cells: Gene induction by vitamin D via a p53-dependent mechanism and inhibition of prostate cancer cell growth. J Cell Physiol 208:566–74

 PubMed Web of Science ®Google Scholar

Lee HJ, Liu H, Goodman C, et al. (2006). Gene expression profiling changes induced by a novel Gemini vitamin D derivative during the progression of breast cancer. Biochem Pharmacol 72:332–43

 PubMedGoogle Scholar

Larriba MJ, González-Sancho JM, Barbáchano A, et al. (2013). Vitamin D is a multilevel repressor of wnt/b-catenin signaling in cancer cells. Cancers (Basel) 5:1242–60

 PubMedGoogle Scholar

Xu H, Posner GH, Stevenson M, Campbell FC. (2010). Apc(MIN) modulation of vitamin D secosteroid growth control. Carcinogenesis 31:1434–41

 PubMedGoogle Scholar

Pálmer HG, González-Sancho JM, Espada J, et al. (2001). Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 154:369–87

 PubMed Web of Science ®Google Scholar

Shah S, Islam MN, Dakshanamurthy S, et al. (2006). The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell 21:799–809

 PubMed Web of Science ®Google Scholar

Beildeck ME, Islam M, Shah S, et al. (2009). Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines. PLoS One 4:e7872

 Google Scholar

Pendás-Franco N, García JM, Peña C, et al. (2008b). DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3. Oncogene 27:4467–77

 PubMed Web of Science ®Google Scholar

Pendás-Franco N, Aguilera O, Pereira F, et al. (2008a). Vitamin D and Wnt/beta-catenin pathway in colon cancer: Role and regulation of DICKKOPF genes. Anticancer Res 28:2613–23

 PubMed Web of Science ®Google Scholar

Lopes N, Carvalho J, Durães C, et al. (2012). 1 Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation. Anticancer Res 32:249–57

 PubMed Web of Science ®Google Scholar

Gocek E, Studzinski GP. (2009). Vitamin D and differentiation in cancer. Crit Rev Clin Lab Sci 46:190–209

 PubMed Web of Science ®Google Scholar

Pendás-Franco N, González-Sancho JM, Suárez Y, et al. (2007). Vitamin D regulates the phenotype of human breast cancer cells. Differentiation 75:193–207

 PubMed Web of Science ®Google Scholar

Krishnan AV, Shinghal R, Raghavachari N, et al. (2004). Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays. Prostate 59:243–51

 PubMed Web of Science ®Google Scholar

Xiao W, Hodge DR, Wang L, et al. (2004). Co-operative functions between nuclear factors NFκB and CCAT/enhancer-binding protein-β (C/EBP-β) regulate the IL-6 promoter in autocrine human prostate cancer cells. Prostate 61:354–70

 PubMedGoogle Scholar

Hughes PJ, Marcinkowska E, Gocek E, et al. (2010). Vitamin D3-driven signals for myeloid cell differentiation-implications for differentiation therapy. Leuk Res 34:553–65

 PubMed Web of Science ®Google Scholar

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 Web of Science ®Google Scholar

Díaz GD, Paraskeva C, Thomas MG, et al. (2000). Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: Possible implications for prevention and therapy. Cancer Res 60:2304–12

 PubMed Web of Science ®Google Scholar

Pan L, Matloob AF, Du J, et al. (2010). Vitamin D stimulates apoptosis in gastric cancer cells in synergy with trichostatin A/sodium butyrate-induced and 5-aza-2′-deoxycytidine-induced PTEN upregulation. FEBS J 277:989–99

 PubMed Web of Science ®Google Scholar

Sergeev IN. (2012). Vitamin D and cellular Ca2+ signaling in breast cancer. Anticancer Res 32:299–302

 PubMed Web of Science ®Google Scholar

Mathiasen IS, Lademann U, Jäättelä M. (1999). Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. Cancer Res 59:4848–56

 PubMed Web of Science ®Google Scholar

Høyer-Hansen M, Bastholm L, Szyniarowski P, et al. (2007). Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25:193–205

 PubMed Web of Science ®Google Scholar

Wang J, Lian H, Zhao Y, et al. (2008). Vitamin D3 induces autophagy of human myeloid leukemia cells. J Biol Chem 12:25596–605

 Google Scholar

Hoyer-Hansen M, Nordbrandt SP, Jäättelä M. (2010). Autophagy as a basis for the health-promoting effects of vitamin D. Trends Mol Med 16:295–302

 PubMed Web of Science ®Google Scholar

Høyer-Hansen M, Bastholm L, Mathiasen IS, et al. (2005). Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ 12:1297–309

 PubMed Web of Science ®Google Scholar

Tavera-Mendoza L, Wang TT, Lallemant B, et al. (2006). Convergence of vitamin D and retinoic acid signalling at a common hormone response element. EMBO Rep 7:180–5

 Google Scholar

Stubbs JR, Idiculla A, Slusser J, et al. (2010). Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol 21:353–61

 PubMed Web of Science ®Google Scholar

Wu S, Sun J. (2011). Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med 11:325–35

 PubMed Web of Science ®Google Scholar

Bao BY, Ting HJ, Hsu JW, et al. (2010). Down-regulation of NF-kappaB signals is involved in loss of 1alpha,25-dihydroxyvitamin D3 responsiveness. J Steroid Biochem Mol Biol 120:11–21

 PubMedGoogle Scholar

Krishnan AV, Feldman D. (2010). Molecular pathways mediating the anti-inflammatory effects of calcitriol: Implications for prostate cancer chemoprevention and treatment. Endocr Relat Cancer 17:19–38

 PubMedGoogle Scholar

Tse AK, Zhu GY, Wan CK, et al. (2010). 1Alpha,25-Dihydroxyvitamin D3 inhibits transcriptional potential of nuclear factor kappa B in breast cancer cells. Mol Immunol 47:1728–38

 PubMedGoogle Scholar

Janjetovic Z, Brozyna AA, Tuckey RC, et al. (2011). High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives. Br J Cancer 105:1874–84

 PubMedGoogle Scholar

Kovalenko PL, Zhang Z, Cui M, et al. (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 Web of Science ®Google Scholar

Zhang X, Li P, Bao J, et al. (2005). Suppression of death receptor-mediated apoptosis by 1,25-dihydroxyvitamin D3 revealed by microarray analysis. J Biol Chem 280:35458–68

 PubMedGoogle Scholar

Bao BY, Ting HJ, Hsu JW, Lee YF. (2008). Protective role of 1 alpha,25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int J Cancer 122:2699–706

 PubMed Web of Science ®Google Scholar

Nair-Shalliker V, Armstrong BK, Fenech M. (2012). Does vitamin D protect against DNA damage? Mutat Res 733:50–7

 PubMed Web of Science ®Google Scholar

Akhter J, Chen X, Bowrey P, et al. (1997). Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model. Dis Colon Rectum 40:317–21

 PubMedGoogle Scholar

Jiang F, Li P, Fornace AJ Jr, et al. (2003a). G2/M arrest by 1,25-dihydroxyvitamin D3 in ovarian cancer cells mediated through the induction of GADD45 via an exonic enhancer. J Biol Chem 278:48030–40

 PubMed Web of Science ®Google Scholar

Ting HJ, Yasmin-Karim S, Yan SJ, et al. (2012). A positive feedback signaling loop between ATM and the vitamin D receptor is critical for cancer chemoprevention by vitamin D. Cancer Res 72:958–68

 Google Scholar

Gonzalo S. (2014). Novel roles of 1α,25(OH)2D3 on DNA repair provide new strategies for breast cancer treatment. J Steroid Biochem Mol Biol 144:59–64

 Google Scholar

Moreno J, Krishnan AV, Peehl DM, Feldman D. (2006). Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: Inhibition of the prostaglandin pathway. Anticancer Res 26:2525–30

 PubMed Web of Science ®Google Scholar

Moreno J, Krishnan AV, Swami S, et al. (2005). Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res 65:7917–25

 PubMed Web of Science ®Google Scholar

Cordes T, Hoellen, Dittmer C, et al. (2012). Correlation of prostaglandin metabolizing enzymes and serum PGE2 levels with vitamin D receptor and serum 25 (OH) 2D3 levels in breast and ovarian cancer. Anticancer Res 32:351–7

 PubMedGoogle Scholar

Thill M, Hoellen F, Becker S, et al. (2012). Expression of prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cells. Anticancer Res 32:367–72

 PubMedGoogle Scholar

Yuan L, Jiang R, Yang Y, et al. (2012). 1,25-Dihydroxyvitamin D3 inhibits growth of the breast cancer cell line MCF-7 and downregulates cytochrome P4501B1 through the COX-2/PGE2 pathway. Oncol Rep 28:2131–7

 PubMedGoogle Scholar

Mantell DJ, Owens PE, Bundred NJ, et al. (2000). 1Alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res 87:214–20

 PubMed Web of Science ®Google Scholar

Ben-Shoshan M, Amir S, Dang DT, et al. (2007). 1 Alpha,25 dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther 6:1433–9

 PubMed Web of Science ®Google Scholar

Bao BY, Yao J, Lee YF. (2006). 1Alpha,25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis 27:1883–93

 PubMed Web of Science ®Google Scholar

Fernandez-Garcia NI, Pálmer HG, Garcia M, et al. (2005). 1,25- Dihydroxyvitamin D3 regulates the expression of ld1 and ld2 genes and the angiogenic phenotype of human colon carcinoma cells. Oncogene 24:6533–44

 PubMed Web of Science ®Google Scholar

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 143:2508–14

 PubMed Web of Science ®Google Scholar

Flynn G, Chung I, Yu WD, et al. (2006). Calcitriol (1,25-dihydroxycholecalciferol) selectively inhibits proliferation of freshly isolated tumor-derived endothelial cells and induces apoptosis. Oncology 70:447–57

 PubMed Web of Science ®Google Scholar

Chung I, Wong MK, Flynn G, et al. (2006). Differential antiproliferative effects of calcitriol on tumor-derived and matrigel-derived endothelial cells. Cancer Res 66:8565–73

 PubMed Web of Science ®Google Scholar

Aparna R, Subhashini J, Roy KR, et al. (2008). Selective inhibition of cyclooxygenase-2 (COX-2) by 1alpha,25-dihydroxy-16-ene-23-yne vitamin D3, a less calcemic vitamin D analog. J Cell Biochem 104:1832–42

 PubMedGoogle Scholar

Hewison M. (2011). Vitamin D and innate and adaptive immunity. Vitam Horm 86:23–62

 PubMed Web of Science ®Google Scholar

Gombart AF, Borregaard N, Koeffler HP. (2005). Human cathelicidin antimicrobical peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 19:1067–77

 PubMed Web of Science ®Google Scholar

Bessler H, Djaldetti M. (2012). 1α,25-Dihydroxyvitamin D3 modulates the interaction between immune and colon cancer cells. Biomed Pharmacother 66:428–32

 PubMedGoogle Scholar

Young MR, Day TA. (2013). Immune regulatory activity of vitamin D3 in head and neck cancer. Cancers (Basel) 5:1072–85

 PubMedGoogle Scholar