臺灣博碩士論文加值系統

維他命D本身是沒有活性的，在變成它的活性物1α,25-dihydroxyvitamin D3之前，它需要先到肝臟代謝成25(OH)D3，再到腎臟轉變成1α,25(OH)2D3。1α,25(OH)2D3 會與它的維他命D接受體(VDR)結合，進而影響到基因的表現，至今已知最少有200種基因會受1α,25(OH)2D3的調控，包含發炎，免疫，生殖，心血管系統，神經系統，血管新生，細胞分化及增生，及細胞凋亡等。由於1α,25(OH)2D3對細胞生長的顯著影響，近年來1α,25(OH)2D3已被視為一新的抗癌藥物。仍而，1α,25(OH)2D3的臨床應用卻被它的副作用(高血鈣)所限，為了克服這個限制，已有許多的1α,25(OH)2D3類似物被合成。在我們的實驗裏，我們應用了新一代的1α,25(OH)2D3類似物MART-10(19-nor-2α-(3-hydroxypropyl)-1α, 25-dihydroxyvitamin D3) 來治療乳癌細胞(ER+MCF-7 cells)，我們發現MART-10比1α,25(OH)2D3對於ER+MCF-7 cells的生長有500到1000倍的抑制效果。MART-10及1α,25(OH)2D3對ER+MCF-7 cells 細胞生長周期的阻斷(G0/G1)，同時合併有促進p21 and p27的表現，我們也發現MART-10及1α,25(OH)2D3會藉由改變BAX/Bcl的表現比例而引發cytochrome C的釋放來造成ER+MCF-7 cells的細胞凋亡。我們也應用了MART-10來治療了胰臟癌，MART-10對於胰臟癌細胞生長的抑制作用遠遠的超過了1α,25(OH)2D3，此生長抑制也經由了細胞生長週期的阻斷(G0/G1)，伴隨了p21 and p27的促進及cyclin D3, CDK4, and CDK6的抑制，在動物實驗中，每週2次施打0.3 μg/kg 的MART-10在裸鼠中可有效抑制胰臟癌細胞的生長且不會引起高血鈣。因此，綜合以上的發現，我們認為新一代的1α,25(OH)2D3的類似物MART-10，具有極大潛力成為新的抗癌藥物，值得更進一步的研究。

Vitamin D3 is biologically inert. To become active, it requires two successive hydroxylation steps catalyzed by two cytochrome P450 enzymes, first to synthesize the pro-hormone 25-hydroxyvitamin D3 [25(OH)D3] and then the active hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3]. 1α,25(OH)2D3 has high affinity for the vitamin D receptor (VDR), a transcription factor and a member of the steroid receptor superfamily. Through VDR, 1α,25(OH)2D3 regulates more than 200 genes in mammals, including those involved in the calcium and phosphorus homeostasis, immune function, reproduction, cardiovascular, central nerve system, inflammation, angiogenesis, and cellular proliferation, differentiation and apoptosis. Due to its versatile roles in maintaining and regulating normal cellular phenotypes and functions, 1α,25(OH)2D3 has been implicated as an anti-cancer agent. However, its clinical application is impeded by its side effect- hypercalcemai. To overcome this, thousands of analogs have been synthesized to minimize the hypercalcemia-inducing effect while to maintain or even strengthen its antitumor effect. We investigated the in vitro effects of a new class of less-calcemic 1α,25(OH)2D3 analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), on ER+MCF-7 cells. We demonstrate that MART-10 is 500- to 1000-fold more potent than 1α,25(OH)2D3 in inhibiting cell growth in a dose- and time-dependent manner. MART-10 is also much more potent in arresting MCF-7cell cycle progression at G0/G1 phase as compared to 1α,25(OH)2D3, possibly mediated by a greater induction of p21 and p27 expression. Moreover, MART-10 is more active than 1α,25(OH)2D3 in causing cell apoptosis, likely through a higher BAX/Bcl expression ratio and the subsequent cytochrome C release from mitochondria to cytosol. We also apply MART-10 to treat pancreatic cancer in vitro and in vivo. We have demonstrated that both 1α,25(OH)2D3 and MART-10 exhibited a time- and dose- dependent antiproliferative effect on BxPC-3 cells with MART-10 being much more potent than 1α,25(OH)2D3. The antiproliferative effect was mainly mediated by cell cycle arrest at G0/G1 phases without induction apoptosis as determined by flow cytometry. The induced G0/G1 arrest was associated with upregulation of p21 and p27 and downregulation of cyclin D3, CDK4, and CDK6 as shown by western blot assay. Moreover, treatment with 0.3 μg/kg MART-10 biweekly for three weeks significantly repressed xenografted pancreatic cancer growth without inducing hypercalcemia in vivo. Collectively, based on our finding, MART-10, a new generation of 1α,25(OH)2D3 analog, is deserved to be deemed as a new emerging anticancer regimen.

指導教授推薦書
口試委員會審定書
授權書
誌謝 iv
中文摘要 v
Abstract vii
目錄 ix
List of Figure xiii
List of Table xiv
1. Introduction 1
1.1 Histology of Vitamin D 1
1.2 Functions of Vitamin D 5
1.2.1 Discovery of vitamin D receptor (VDR) 5
1.2.2 The structure and actions of VDR 6
1.2.3 Genomic actions of vitamin D 7
1.3 Antiproliferative effects of vitamin D 10
1.3.1 Cell cycle arrest 13
1.3.2 Hedgehog signaling pathway 15
1.3.3 Insulin-like growth factor-binding protein 3 (IGFBP-3) pathway 17
1.3.4 Transforming Growth factor-beta (TGF-β) pathway 19
1.4 Apoptosis 21
1.5 Anti-angiogenesis 23
1.6 Pro-differentiation 26
1.7 Anti-inflammation 29
1.8 Non-genomic anti-cancer actions of vitamin D 30
1.9 Application of a new brand vitamin D analog (MART-10) to treat ER+ breast cancer cell 33
1.10 Evaluation the therapeutic effect of MART-10 to treat pancreatic cancer in vitro and in vivo 35
2. Objectives 39
3. Materials and Methods 41
3.1 VitaminDcompounds. 41
3.2 Cell culture. 41
3.3 Cell proliferation assay by cell number counting 41
3.4 MTT assay 42
3.5 BrdU assay 42
3.6 Western blot 42
3.7 Real-time qPCR analysis. 44
3.8 Cell cycle analysis with flow cytometry. 45
3.9 Apoptosis analysis by flow cytometry. 45
3.10 Matrigel invasion assay. 46
3.11 Trans-well filter migration assay. 47
3.12 Gelatin Zymography. 47
3.13 Immunohistochemical staining for tissues. 48
3.14 Animal study. 48
3.15 Statistics method 49
4. Results 50
4.1 Application of a new brand vitamin D analog (MART-10) to treat ER+ breast cancer cell 50
4.1.1 VDR expression in ER+ MCF-7 and triple negative MDA-MB-231 cells : 50
4.1.2 Antiproliferative effect of MART-10 and 1α,25(OH)2D3 on MCF-7 and MDA-MB-231 cells 50
4.1.3 Induction of cell cycle arrest at G0/G1phase by MART-10 and 1α,25(OH)2D3 in MCF-7 cells 51
4.1.4 Induction of the cycline dependent kinase (CDK) inhibitors, p21 and p27, in MCF-7 cells by 1α,25 (OH)2D3 and MART-10 52
4.1.5 1α,25(OH)2D3 and MART-10 induced MCF-7 cell apoptosis and potential mechanisms 53
4.1.6 1α,25(OH)2D3 and MART-10 inhibited the invasion and migration of MCF-7 cells 54
4.1.7 Analysis of E-cadherin and MMP- 2 and 9 expression 55
4.1.8 Functional assay of MMPs by zymography 55
4.1.9 Evaluation of CYP24A1 induction by 1α,25(OH)2D3 and MART-10 in MCF-7 cells by RT-qPCR 56
4.1.10 Down regulation of estrogen receptor α (ERα) expression in MCF-7 cells by 1α,25(OH)2D3 and MART-10 57
4.2 Evaluation the therapeutic effect of MART-10 to treat pancreatic cancer in vitro and in vivo 57
4.2.1 Antiproliferative effect of MART-10 and 1α,25(OH)2D3 on BxPC-3 cells 57
4.2.2 Induction of cell cycle arrest at G0/G1 phase by MART-10 and 1α,25(OH)2D3 in BxPC-3 cells 58
4.2.3 Evaluation of Apoptosis Induction of 1α,25 (OH)2D3 and MART-10 in BxPC-3 cells 59
4.2.4 Evaluation of G1 arrest-related cycline dependent kinase (CDK) inhibitors in BxPC-3 cells After treated by 1α,25 (OH)2D3 or MART-10 59
4.2.5 Evaluation of other G1 arrest-related proteins in BxPC-3 cells treated by 1α,25 (OH)2D3 and MART-10 60
4.2.6 Evaluation of in vivo safety of MART-10 administration in nude mice 61
4.2.7 Evaluation of in vivo antitumor effect of 1α,25 (OH)2D3 and MART-10 on BxPC-3 61
4.2.8 Evaluation of G1 arrest related protein expressions in xenografted BxPC3 tumors 62
5. Discussion 63
5.1 MART-10, a new generation of vitamin D analog, is more potent than 1α,25-dihydroxyvitamin D(3) in inhibiting cell proliferation and inducing apoptosis in ER+ MCF-7 breast cancer cells. 63
5.2 Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo 73
6. Summary 79
7. Reference 82












List of Figure
Figure 1: Sources and metabolism of vitamin D 119
Figure 2: The functions and the mechanism of vitamin D actions 120
Figure 3: Effects of 1α,25(OH)2D3 (1,25D) on cell cycle progression 121
Figure 4: Simplified Hedgehog (Hh) pathway and its potential effects on the anti-proliferative action of vitamin D 122
Figure 5: VDR expression and the antiproliferative activity of 1α,25(OH)2D3 and MART-10 in ER+ MCF-7 cells and triple negative 124
Figure 6: Flow cytometry analysis of MCF-7 cells under the influence of 1α,25(OH)2D3 and MART-10 127
Figure 7: Expression of p27 and p21 after treating MCF-7 cells with 1α,25(OH)2D3 or MART-10 for 2 days 129
Figure 8: Effects of 1α,25(OH)2D3 (10-6 M) and MART-10 (10-7M ) two days treatment on MCF-7 cell apoptosis analyzed by flow cytometry with Annexin V-FITC and PI staining 131
Figure 9: The apoptotic effects induced by two days treatment of 10-6M 1α,25(OH)2D3 or 10-7 M MART-10 on MCF-7 cells analyzed by tunnel assays to measure the extent of DNA fragmentation visualized by fluorescence microscopy 133
Figure 10: The effect of 1α,25(OH)2D3 and MART-10 on the expression of Bax, Bcl-2, and cytochrome C in MCF-7 cells 134
Figure 11: The influence of 1α,25(OH)2D3 and MART-10 on MCF-7 cell invasion and migradation 135
Figure 12: The effect of 1α,25(OH)2D3 or MART-10 on the expression of E-cadherin, MMP-2 and MMP-9 136
Figure 13: The time-dependent effect of 1α,25(OH)2D3 and MART-10 on endogenous CYP24A1 mRNA expression in MCF-7 cells 138
Figure 14: Western blot analysis of the expression of ERα after treating MCF-7 cells with 1α,25(OH)2D3 or MART-10 for 2 days 139
Figure 15: The expression of VDR and the antiproliferative activity of 1α,25(OH)2D3 and MART-10 in BxPC-3 cells 140
Figure 16: Flow cytometry analysis of cell cycle distribution for BxPC-3 cells treated by 1α,25(OH)2D3 and MART-10 143
Figure 17: Effects of 1α,25(OH)2D3 and MART-10 on BxPC-3 cell apoptosis analyzed by flow cytometry with Annexin V-FITC and PI staining 144
Figure 18: Western blot analysis for the expressions of G1 arrest-related CKIs after treating MCF-7 cells with 1α,25(OH)2D3 and MART-10 145
Figure 19: In vivo evaluation of MART-10 and 1α,25(OH)2D3 antiproliferative effect on BxPC3 cells and of safety of systemic administration of MART-10 and 1α25(OH)2D3 148
Figure 20: IHC stains for p21, p27 and cyclin D3 expressions in tumors after MART-10 and 1α,25(OH)2D3 treatment 151

List of Table
table 1 126
table 2 132

1. Norman AW, Lund J, Deluca HF (1964) Biologically Active Forms of Vitamin D3 in Kidney and Intestine. Arch Biochem Biophys 108: 12-21.
2. Morii HL, J.; Neville, P.F.; DeLuca, H.F. (1967) Biological activity of a vitamin D metabolite. Arch Biochem Biophys 120: 508-512.
3. Blunt JW, Tanaka Y, DeLuca HF (1968) The biological activity of 25-hydroxycholecalciferol, a metabolite of vitamin D3. Proc Natl Acad Sci U S A 61: 717-718.
4. Lawson DE, Fraser DR, Kodicek E, Morris HR, Williams DH (1971) Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature 230: 228-230.
5. Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, et al. (1971) 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine. Science 173: 51-54.
6. Holick MF, Schnoes HK, DeLuca HF (1971) Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proc Natl Acad Sci U S A 68: 803-804.
7. Holick MF, MacLaughlin JA, Clark MB, Holick SA, Potts JT, Jr., et al. (1980) Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science 210: 203-205.
8. Ponchon G, DeLuca HF (1969) The role of the liver in the metabolism of vitamin D. J Clin Invest 48: 1273-1279.
9. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A 101: 7711-7715.
10. Haddad JG, Jr., Walgate J (1976) 25-Hydroxyvitamin D transport in human plasma. Isolation and partial characterization of calcifidiol-binding protein. J Biol Chem 251: 4803-4809.
11. Bouillon R, Van Baelen H, Tan BK, De Moor P (1980) The isolation and characterization of the 25-hydroxyvitamin D-binding protein from chick serum. J Biol Chem 255: 10925-10930.
12. Schuster I (2011) Cytochromes P450 are essential players in the vitamin D signaling system. Biochim Biophys Acta 1814: 186-199.
13. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, et al. (2001) Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86: 888-894.
14. Shultz TD, Fox J, Heath H, 3rd, Kumar R (1983) Do tissues other than the kidney produce 1,25-dihydroxyvitamin D3 in vivo? A reexamination. Proc Natl Acad Sci U S A 80: 1746-1750.
15. Reeve L, Tanaka Y, DeLuca HF (1983) Studies on the site of 1,25-dihydroxyvitamin D3 synthesis in vivo. J Biol Chem 258: 3615-3617.
16. Mawer EB, Backhouse J, Lumb GA, Stanbury SW (1971) Evidence for formation of 1,25-dihydroxycholecalciferol during metabolism of vitamin D in man. Nat New Biol 232: 188-189.
17. Gray RW, Weber HP, Dominguez JH, Lemann J, Jr. (1974) The metabolism of vitamin D3 and 25-hydroxyvitamin D3 in normal and anephric humans. J Clin Endocrinol Metab 39: 1045-1056.
18. Catto GR, Muirhead N (1984) Metabolic consequences of bilateral nephrectomy. Br Med J (Clin Res Ed) 289: 146-147.
19. Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF (1979) Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 206: 1188-1190.
20. Colston K, Hirt M, Feldman D (1980) Organ distribution of the cytoplasmic 1,25-dihydroxycholecalciferol receptor in various mouse tissues. Endocrinology 107: 1916-1922.
21. Chen TC, DeLuca HF (1973) Receptors of 1,25-dikydroxycholecalciferol in rat intestine. J Biol Chem 248: 4890-4895.
22. Tsai HC, Wong RG, Norman AW (1972) Studies on calciferol metabolism. IV. Subcellular localization of 1,25-dihydroxy-vitamin D 3 in intestinal mucosa and correlation with increased calcium transport. J Biol Chem 247: 5511-5519.
23. Brumbaugh PF, Haussler MR (1975) Specific binding of 1alpha,25-dihydroxycholecalciferol to nuclear components of chick intestine. J Biol Chem 250: 1588-1594.
24. Brumbaugh PF, Hughes MR, Haussler MR (1975) Cytoplasmic and nuclear binding components for 1alpha25-dihydroxyvitamin D3 in chick parathyroid glands. Proc Natl Acad Sci U S A 72: 4871-4875.
25. McDonnell DP, Mangelsdorf DJ, Pike JW, Haussler MR, O'Malley BW (1987) Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science 235: 1214-1217.
26. Burmester JK, Maeda N, DeLuca HF (1988) Isolation and expression of rat 1,25-dihydroxyvitamin D3 receptor cDNA. Proc Natl Acad Sci U S A 85: 1005-1009.
27. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, et al. (1988) Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A 85: 3294-3298.
28. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, et al. (1998) The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 13: 325-349.
29. Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D (2000) The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell 5: 173-179.
30. Hsieh JC, Jurutka PW, Galligan MA, Terpening CM, Haussler CA, et al. (1991) Human vitamin D receptor is selectively phosphorylated by protein kinase C on serine 51, a residue crucial to its trans-activation function. Proc Natl Acad Sci U S A 88: 9315-9319.
31. Jurutka PW, Hsieh JC, MacDonald PN, Terpening CM, Haussler CA, et al. (1993) Phosphorylation of serine 208 in the human vitamin D receptor. The predominant amino acid phosphorylated by casein kinase II, in vitro, and identification as a significant phosphorylation site in intact cells. J Biol Chem 268: 6791-6799.
32. Haussler MR, Haussler CA, Jurutka PW, Thompson PD, Hsieh JC, et al. (1997) The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J Endocrinol 154 Suppl: S57-73.
33. Tsai MJ, O'Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63: 451-486.
34. Freedman LP (1999) Increasing the complexity of coactivation in nuclear receptor signaling. Cell 97: 5-8.
35. Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM (1999) Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 98: 675-686.
36. Battaglia S, Maguire O, Campbell MJ (2010) Transcription factor co-repressors in cancer biology: roles and targeting. Int J Cancer 126: 2511-2519.
37. Dilworth FJ, Chambon P (2001) Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription. Oncogene 20: 3047-3054.
38. Haussler MR, Jurutka PW, Mizwicki M, Norman AW (2011) Vitamin D receptor (VDR)-mediated actions of 1alpha,25(OH)vitamin D: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab 25: 543-559.
39. Jin CH, Kerner SA, Hong MH, Pike JW (1996) Transcriptional activation and dimerization functions in the human vitamin D receptor. Mol Endocrinol 10: 945-957.
40. Pike JW, Meyer MB, Watanuki M, Kim S, Zella LA, et al. (2007) Perspectives on mechanisms of gene regulation by 1,25-dihydroxyvitamin D3 and its receptor. J Steroid Biochem Mol Biol 103: 389-395.
41. Zhang J, Chalmers MJ, Stayrook KR, Burris LL, Wang Y, et al. (2011) DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nat Struct Mol Biol 18: 556-563.
42. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, et al. (2008) Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 456: 350-356.
43. Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126-2132.
44. Rastinejad F, Perlmann T, Evans RM, Sigler PB (1995) Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375: 203-211.
45. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, et al. (2010) A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res 20: 1352-1360.
46. Chen TC, Holick MF (2003) Vitamin D and prostate cancer prevention and treatment. Trends Endocrinol Metab 14: 423-430.
47. Stewart LV, Weigel NL (2004) Vitamin D and prostate cancer. Exp Biol Med (Maywood) 229: 277-284.
48. Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94: 26-34.
49. Adams JS, Hewison M (2010) Update in vitamin D. J Clin Endocrinol Metab 95: 471-478.
50. Chiang KC, Yeh CN, Chen MF, Chen TC (2011) Hepatocellular carcinoma and vitamin D: a review. J Gastroenterol Hepatol 26: 1597-1603.
51. Krishnan AV, Feldman D (2011) Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 51: 311-336.
52. Fleet JC, DeSmet M, Johnson R, Li Y (2012) Vitamin D and cancer: a review of molecular mechanisms. Biochem J 441: 61-76.
53. Miller GJ (1998) Vitamin D and prostate cancer: biologic interactions and clinical potentials. Cancer Metastasis Rev 17: 353-360.
54. Zinser GM, McEleney K, Welsh J (2003) Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockout mice. Mol Cell Endocrinol 200: 67-80.
55. Malumbres M (2011) Physiological relevance of cell cycle kinases. Physiol Rev 91: 973-1007.
56. Canavese M, Santo L, Raje N (2012) Cyclin dependent kinases in cancer: potential for therapeutic intervention. Cancer Biol Ther 13: 451-457.
57. Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1: 222-231.
58. Jiang H, Lin J, Su ZZ, Collart FR, Huberman E, et al. (1994) Induction of differentiation in human promyelocytic HL-60 leukemia cells activates p21, WAF1/CIP1, expression in the absence of p53. Oncogene 9: 3397-3406.
59. Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP (1996) Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev 10: 142-153.
60. Saramaki A, Banwell CM, Campbell MJ, Carlberg C (2006) Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res 34: 543-554.
61. Kawa S, Yoshizawa K, Tokoo M, Imai H, Oguchi H, et al. (1996) Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer cell lines. Gastroenterology 110: 1605-1613.
62. Kawa S, Nikaido T, Aoki Y, Zhai Y, Kumagai T, et al. (1997) Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines. Br J Cancer 76: 884-889.
63. Yang ES, Maiorino CA, Roos BA, Knight SR, Burnstein KL (2002) Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. Mol Cell Endocrinol 186: 69-79.
64. 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: 46862-46868.
65. Luo W, Chen Y, Liu M, Du K, Zheng G, et al. (2009) EB1089 induces Skp2-dependent p27 accumulation, leading to cell growth inhibition and cell cycle G1 phase arrest in human hepatoma cells. Cancer Invest 27: 29-37.
66. 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.
67. Uhmann A, Niemann H, Lammering B, Henkel C, Hess I, et al. (2011) Antitumoral effects of calcitriol in basal cell carcinomas involve inhibition of hedgehog signaling and induction of vitamin D receptor signaling and differentiation. Mol Cancer Ther 10: 2179-2188.
68. Teichert AE, Elalieh H, Elias PM, Welsh J, Bikle DD (2011) Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice. J Invest Dermatol 131: 2289-2297.
69. Tang JY, Xiao TZ, Oda Y, Chang KS, Shpall E, et al. (2011) Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas. Cancer Prev Res (Phila) 4: 744-751.
70. Yanagisawa J, Yanagi Y, Masuhiro Y, Suzawa M, Watanabe M, et al. (1999) Convergence of transforming growth factor-beta and vitamin D signaling pathways on SMAD transcriptional coactivators. Science 283: 1317-1321.
71. 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: 137-143.
72. Tong WM, Hofer H, Ellinger A, Peterlik M, Cross HS (1999) Mechanism of antimitogenic action of vitamin D in human colon carcinoma cells: relevance for suppression of epidermal growth factor-stimulated cell growth. Oncol Res 11: 77-84.
73. Moreno J, Krishnan AV, Feldman D (2005) Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer. J Steroid Biochem Mol Biol 97: 31-36.
74. Nusslein-Volhard C, Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287: 795-801.
75. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, et al. (1993) Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75: 1417-1430.
76. Krauss S, Concordet JP, Ingham PW (1993) A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75: 1431-1444.
77. Riddle RD, Johnson RL, Laufer E, Tabin C (1993) Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75: 1401-1416.
78. Chang DT, Lopez A, von Kessler DP, Chiang C, Simandl BK, et al. (1994) Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120: 3339-3353.
79. Roelink H, Augsburger A, Heemskerk J, Korzh V, Norlin S, et al. (1994) Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76: 761-775.
80. Yang L, Xie G, Fan Q, Xie J (2010) Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 29: 469-481.
81. Bale AE (2002) Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet 3: 47-65.
82. Epstein EH (2008) Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer 8: 743-754.
83. Mimeault M, Batra SK (2010) Frequent deregulations in the hedgehog signaling network and cross-talks with the epidermal growth factor receptor pathway involved in cancer progression and targeted therapies. Pharmacol Rev 62: 497-524.
84. Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, et al. (2006) Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol 4: e232.
85. Moriwake T, Tanaka H, Kanzaki S, Higuchi J, Seino Y (1992) 1,25-Dihydroxyvitamin D3 stimulates the secretion of insulin-like growth factor binding protein 3 (IGFBP-3) by cultured human osteosarcoma cells. Endocrinology 130: 1071-1073.
86. Velez-Yanguas MC, Kalebic T, Maggi M, Kappel CC, Letterio J, et al. (1996) 1 alpha, 25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531) modulation of insulin-like growth factor-binding protein-3 and induction of differentiation and growth arrest in a human osteosarcoma cell line. J Clin Endocrinol Metab 81: 93-99.
87. 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: 157-162.
88. 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: 223-229.
89. Agarwal C, Lambert A, Chandraratna RA, Rorke EA, Eckert RL (1999) Vitamin D regulates human ectocervical epithelial cell proliferation and insulin-like growth factor-binding protein-3 level. Biol Reprod 60: 567-572.
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.
91. Sprenger CC, Peterson A, Lance R, Ware JL, Drivdahl RH, 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: 609-618.
92. 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.
93. 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: 282-291.
94. 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.
95. 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: 5521-5532.
96. Malinen M, Ryynanen J, Heinaniemi M, Vaisanen S, Carlberg C (2011) Cyclical regulation of the insulin-like growth factor binding protein 3 gene in response to 1alpha,25-dihydroxyvitamin D3. Nucleic Acids Res 39: 502-512.
97. Peng L, Malloy PJ, Wang J, Feldman D (2006) Growth inhibitory concentrations of androgens up-regulate insulin-like growth factor binding protein-3 expression via an androgen response element in LNCaP human prostate cancer cells. Endocrinology 147: 4599-4607.
98. Yanagi Y, Suzawa M, Kawabata M, Miyazono K, Yanagisawa J, et al. (1999) Positive and negative modulation of vitamin D receptor function by transforming growth factor-beta signaling through smad proteins. J Biol Chem 274: 12971-12974.
99. Wu Y, Craig TA, Lutz WH, Kumar R (1999) Identification of 1 alpha,25-dihydroxyvitamin D3 response elements in the human transforming growth factor beta 2 gene. Biochemistry 38: 2654-2660.
100. Wu G, Fan RS, Li W, Srinivas V, Brattain MG (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: 7749-7756.
101. 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: 1540-1546.
102. Proietti S, Cucina A, D'Anselmi F, Dinicola S, Pasqualato A, et al. (2011) Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFbeta-1-dependent growth inhibition of breast cancer cells. J Pineal Res 50: 150-158.
103. Daniel C, Schroder O, Zahn N, Gaschott T, Steinhilber D, et al. (2007) The TGFbeta/Smad 3-signaling pathway is involved in butyrate-mediated vitamin D receptor (VDR)-expression. J Cell Biochem 102: 1420-1431.
104. Ramirez AM, Wongtrakool C, Welch T, Steinmeyer A, Zugel U, et al. (2010) Vitamin D inhibition of pro-fibrotic effects of transforming growth factor beta1 in lung fibroblasts and epithelial cells. J Steroid Biochem Mol Biol 118: 142-150.
105. Halder SK, Goodwin JS, Al-Hendy A (2011) 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 96: E754-762.
106. Debatin KM (2004) Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother 53: 153-159.
107. Jendrossek V (2012) The intrinsic apoptosis pathways as a target in anticancer therapy. Curr Pharm Biotechnol 13: 1426-1438.
108. McDonnell TJ, Beham A, Sarkiss M, Andersen MM, Lo P (1996) Importance of the Bcl-2 family in cell death regulation. Experientia 52: 1008-1017.
109. Herrmann JL, Bruckheimer E, McDonnell TJ (1996) Cell death signal transduction and Bcl-2 function. Biochem Soc Trans 24: 1059-1065.
110. 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.
111. Polek TC, Stewart LV, Ryu EJ, Cohen MB, Allegretto EA, et al. (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.
112. Deeb KK, Trump DL, Johnson CS (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7: 684-700.
113. James SY, Mackay AG, Colston KW (1996) Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. J Steroid Biochem Mol Biol 58: 395-401.
114. Simboli-Campbell M, Narvaez CJ, Tenniswood M, Welsh J (1996) 1,25-Dihydroxyvitamin D3 induces morphological and biochemical markers of apoptosis in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 58: 367-376.
115. Gown AM, Willingham MC (2002) Improved detection of apoptotic cells in archival paraffin sections: immunohistochemistry using antibodies to cleaved caspase 3. J Histochem Cytochem 50: 449-454.
116. Duan WR, Garner DS, Williams SD, Funckes-Shippy CL, Spath IS, et al. (2003) Comparison of immunohistochemistry for activated caspase-3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC-3 subcutaneous xenografts. J Pathol 199: 221-228.
117. Resendes AR, Majo N, Segales J, Mateu E, Calsamiglia M, et al. (2004) Apoptosis in lymphoid organs of pigs naturally infected by porcine circovirus type 2. J Gen Virol 85: 2837-2844.
118. Chiang KC, Yeh CN, Chen HY, Lee JM, Juang HH, et al. (2011) 19-Nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 (MART-10) is a potent cell growth regulator with enhanced chemotherapeutic potency in liver cancer cells. Steroids 76: 1513-1519.
119. Jiang F, Bao J, Li P, Nicosia SV, Bai W (2004) Induction of ovarian cancer cell apoptosis by 1,25-dihydroxyvitamin D3 through the down-regulation of telomerase. J Biol Chem 279: 53213-53221.
120. Ylikomi T, Laaksi I, Lou YR, Martikainen P, Miettinen S, et al. (2002) Antiproliferative action of vitamin D. Vitam Horm 64: 357-406.
121. Chaudhry M, Sundaram S, Gennings C, Carter H, Gewirtz DA (2001) The vitamin D3 analog, ILX-23-7553, enhances the response to adriamycin and irradiation in MCF-7 breast tumor cells. Cancer Chemother Pharmacol 47: 429-436.
122. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6: 273-286.
123. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27-31.
124. Adair TH, Gay WJ, Montani JP (1990) Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am J Physiol 259: R393-404.
125. Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359: 843-845.
126. Giaccia A, Siim BG, Johnson RS (2003) HIF-1 as a target for drug development. Nat Rev Drug Discov 2: 803-811.
127. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57-70.
128. Rankin EB, Giaccia AJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15: 678-685.
129. Ferrara N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280: C1358-1366.
130. Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25: 581-611.
131. Ferrara N (2010) Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev 21: 21-26.
132. Cao Y, Cao R, Hedlund EM (2008) R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med (Berl) 86: 785-789.
133. Jost M, Folgueras AR, Frerart F, Pendas AM, Blacher S, et al. (2006) Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice. Cancer Res 66: 5234-5241.
134. Merke J, Milde P, Lewicka S, Hugel U, Klaus G, et al. (1989) Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest 83: 1903-1915.
135. Iseki K, Tatsuta M, Uehara H, Iishi H, Yano H, et al. (1999) Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer 81: 730-733.
136. 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.
137. Chung I, Wong MK, Flynn G, Yu WD, Johnson CS, et al. (2006) Differential antiproliferative effects of calcitriol on tumor-derived and matrigel-derived endothelial cells. Cancer Res 66: 8565-8573.
138. Lin R, Nagai Y, Sladek R, Bastien Y, Ho J, 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: 1243-1256.
139. Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, et al. (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.
140. Fernandez-Garcia NI, Palmer HG, Garcia M, Gonzalez-Martin A, del Rio M, et al. (2005) 1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells. Oncogene 24: 6533-6544.
141. Bao BY, Yao J, Lee YF (2006) 1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis 27: 1883-1893.
142. Getzenberg RH, Light BW, Lapco PE, Konety BR, Nangia AK, et al. (1997) Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology 50: 999-1006.
143. Nakagawa K, Sasaki Y, Kato S, Kubodera N, Okano T (2005) 22-Oxa-1alpha,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis 26: 1044-1054.
144. Cardus A, Parisi E, Gallego C, Aldea M, Fernandez E, et al. (2006) 1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway. Kidney Int 69: 1377-1384.
145. Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, et al. (1981) Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A 78: 4990-4994.
146. Palmer HG, Sanchez-Carbayo M, Ordonez-Moran P, Larriba MJ, Cordon-Cardo C, et al. (2003) Genetic signatures of differentiation induced by 1alpha,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res 63: 7799-7806.
147. Akutsu N, Lin R, Bastien Y, Bestawros A, Enepekides DJ, et al. (2001) Regulation of gene Expression by 1alpha,25-dihydroxyvitamin D3 and Its analog EB1089 under growth-inhibitory conditions in squamous carcinoma Cells. Mol Endocrinol 15: 1127-1139.
148. Guzey M, Luo J, Getzenberg RH (2004) Vitamin D3 modulated gene expression patterns in human primary normal and cancer prostate cells. J Cell Biochem 93: 271-285.
149. Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, 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: 369-387.
150. Lazzaro G, Agadir A, Qing W, Poria M, Mehta RR, et al. (2000) Induction of differentiation by 1alpha-hydroxyvitamin D(5) in T47D human breast cancer cells and its interaction with vitamin D receptors. Eur J Cancer 36: 780-786.
151. Pendas-Franco N, Gonzalez-Sancho JM, Suarez Y, Aguilera O, Steinmeyer A, et al. (2007) Vitamin D regulates the phenotype of human breast cancer cells. Differentiation 75: 193-207.
152. Haselberger M, Springwald A, Konwisorz A, Lattrich C, Goerse R, et al. (2011) Silencing of the icb-1 gene inhibits the induction of differentiation-associated genes by vitamin D3 and all-trans retinoic acid in gynecological cancer cells. Int J Mol Med 28: 121-127.
153. Hsu JW, Yasmin-Karim S, King MR, Wojciechowski JC, Mickelsen D, et al. (2011) Suppression of prostate cancer cell rolling and adhesion to endothelium by 1alpha,25-dihydroxyvitamin D3. Am J Pathol 178: 872-880.
154. Lopes N, Carvalho J, Duraes C, Sousa B, Gomes M, et al. (2012) 1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation. Anticancer Res 32: 249-257.
155. Barbachano A, Ordonez-Moran P, Garcia JM, Sanchez A, Pereira F, et al. (2010) SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity. Oncogene 29: 4800-4813.
156. Pendas-Franco N, Garcia JM, Pena C, Valle N, Palmer HG, et al. (2008) 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: 4467-4477.
157. Pendas-Franco N, Aguilera O, Pereira F, Gonzalez-Sancho JM, Munoz A (2008) Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Res 28: 2613-2623.
158. Shah S, Islam MN, Dakshanamurthy S, Rizvi I, Rao M, et al. (2006) The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell 21: 799-809.
159. Meyer MB, Goetsch PD, Pike JW (2012) VDR/RXR and TCF4/beta-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression. Mol Endocrinol 26: 37-51.
160. Welsh J (2012) Cellular and molecular effects of vitamin D on carcinogenesis. Arch Biochem Biophys 523: 107-114.
161. Kaler P, Augenlicht L, Klampfer L (2009) Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene 28: 3892-3902.
162. Peehl DM, Shinghal R, Nonn L, Seto E, Krishnan AV, 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: 131-141.
163. Krishnan AV, Shinghal R, Raghavachari N, Brooks JD, Peehl DM, et al. (2004) Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays. Prostate 59: 243-251.
164. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454: 436-444.
165. Norman AW, Song X, Zanello L, Bula C, Okamura WH (1999) Rapid and genomic biological responses are mediated by different shapes of the agonist steroid hormone, 1alpha,25(OH)2vitamin D3. Steroids 64: 120-128.
166. Zanello LP, Norman AW (2004) Rapid modulation of osteoblast ion channel responses by 1alpha,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. Proc Natl Acad Sci U S A 101: 1589-1594.
167. Wali RK, Kong J, Sitrin MD, Bissonnette M, Li YC (2003) Vitamin D receptor is not required for the rapid actions of 1,25-dihydroxyvitamin D3 to increase intracellular calcium and activate protein kinase C in mouse osteoblasts. J Cell Biochem 88: 794-801.
168. Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW (2004) The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol 18: 2660-2671.
169. Mizwicki MT, Keidel D, Bula CM, Bishop JE, Zanello LP, et al. (2004) Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1alpha,25(OH)2-vitamin D3 signaling. Proc Natl Acad Sci U S A 101: 12876-12881.
170. Hanada K, Sawamura D, Nakano H, Hashimoto I (1995) Possible role of 1,25-dihydroxyvitamin D3-induced metallothionein in photoprotection against UVB injury in mouse skin and cultured rat keratinocytes. J Dermatol Sci 9: 203-208.
171. Wong G, Gupta R, Dixon KM, Deo SS, Choong SM, et al. (2004) 1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway. J Steroid Biochem Mol Biol 89-90: 567-570.
172. De Haes P, Garmyn M, Verstuyf A, De Clercq P, Vandewalle M, et al. (2005) 1,25-Dihydroxyvitamin D3 and analogues protect primary human keratinocytes against UVB-induced DNA damage. J Photochem Photobiol B 78: 141-148.
173. Banakar MC, Paramasivan SK, Chattopadhyay MB, Datta S, Chakraborty P, et al. (2004) 1alpha, 25-dihydroxyvitamin D3 prevents DNA damage and restores antioxidant enzymes in rat hepatocarcinogenesis induced by diethylnitrosamine and promoted by phenobarbital. World J Gastroenterol 10: 1268-1275.
174. Mason RS, Sequeira VB, Dixon KM, Gordon-Thomson C, Pobre K, et al. (2010) Photoprotection by 1alpha,25-dihydroxyvitamin D and analogs: further studies on mechanisms and implications for UV-damage. J Steroid Biochem Mol Biol 121: 164-168.
175. Wu-Wong JR, Nakane M, Ma J, Ruan X, Kroeger PE (2006) Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis 186: 20-28.
176. Ting HJ, Yasmin-Karim S, Yan SJ, Hsu JW, Lin TH, 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: 958-968.
177. Jemal A, Bray F, Center MM, Ferlay J, Ward E, et al. (2011) Global cancer statistics. CA Cancer J Clin 61: 69-90.
178. Toft D, Gorski J (1966) A receptor molecule for estrogens: isolation from the rat uterus and preliminary characterization. Proc Natl Acad Sci U S A 55: 1574-1581.
179. Toft D, Shyamala G, Gorski J (1967) A receptor molecule for estrogens: studies using a cell-free system. Proc Natl Acad Sci U S A 57: 1740-1743.
180. Zwart W, Theodorou V, Carroll JS (2011) Estrogen receptor-positive breast cancer: a multidisciplinary challenge. Wiley Interdiscip Rev Syst Biol Med 3: 216-230.
181. Holm C, Kok M, Michalides R, Fles R, Koornstra RH, et al. (2009) Phosphorylation of the oestrogen receptor alpha at serine 305 and prediction of tamoxifen resistance in breast cancer. J Pathol 217: 372-379.
182. Chiang KC, Chen TC (2009) Vitamin D for the prevention and treatment of pancreatic cancer. World J Gastroenterol 15: 3349-3354.
183. Chiang KC, Yeh CN, Chen MF, Chen TC (2011) Hepatocellular carcinoma and vitamin D: a review. J Gastroenterol Hepatol 26: 1597-1603.
184. Cross HS, Kallay E (2009) Regulation of the colonic vitamin D system for prevention of tumor progression: an update. Future Oncol 5: 493-507.
185. Welsh J (2012) Cellular and molecular effects of vitamin D on carcinogenesis. Arch Biochem Biophys 523: 107-114.
186. Bouillon R, Verstuyf A, Verlinden L, Allewaert K, Branisteanu D, et al. (1995) Non-hypercalcemic pharmacological aspects of vitamin D analogs. Biochem Pharmacol 50: 577-583.
187. Guyton KZ, Kensler TW, Posner GH (2001) Cancer chemoprevention using natural vitamin D and synthetic analogs. Annu Rev Pharmacol Toxicol 41: 421-442.
188. Jensen SS, Madsen MW, Lukas J, Binderup L, Bartek J (2001) Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery. Mol Endocrinol 15: 1370-1380.
189. Sundaram S, Chaudhry M, Reardon D, Gupta M, Gewirtz DA (2000) The vitamin D3 analog EB 1089 enhances the antiproliferative and apoptotic effects of adriamycin in MCF-7 breast tumor cells. Breast Cancer Res Treat 63: 1-10.
190. Abe-Hashimoto J, Kikuchi T, Matsumoto T, Nishii Y, Ogata E, et al. (1993) Antitumor effect of 22-oxa-calcitriol, a noncalcemic analogue of calcitriol, in athymic mice implanted with human breast carcinoma and its synergism with tamoxifen. Cancer Res 53: 2534-2537.
191. Koshizuka K, Koike M, Asou H, Cho SK, Stephen T, et al. (1999) Combined effect of vitamin D3 analogs and paclitaxel on the growth of MCF-7 breast cancer cells in vivo. Breast Cancer Res Treat 53: 113-120.
192. Bower M, Colston KW, Stein RC, Hedley A, Gazet JC, et al. (1991) Topical calcipotriol treatment in advanced breast cancer. Lancet 337: 701-702.
193. Gulliford T, English J, Colston KW, Menday P, Moller S, et al. (1998) A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer. Br J Cancer 78: 6-13.
194. Ono K, Yoshida A, Saito N, Fujishima T, Honzawa S, et al. (2003) Efficient synthesis of 2-modified 1alpha,25-dihydroxy-19-norvitamin D3 with Julia olefination: high potency in induction of differentiation on HL-60 cells. J Org Chem 68: 7407-7415.
195. Flanagan JN, Zheng S, Chiang KC, Kittaka A, Sakaki T, et al. (2009) Evaluation of 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 as a therapeutic agent for androgen-dependent prostate cancer. Anticancer Res 29: 3547-3553.
196. Chen TC, Persons KS, Zheng S, Mathieu J, Holick MF, et al. (2007) Evaluation of C-2-substituted 19-nor-1alpha,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer. J Steroid Biochem Mol Biol 103: 717-720.
197. Iglesias-Gato D, Zheng S, Flanagan JN, Jiang L, Kittaka A, et al. (2011) Substitution at carbon 2 of 19-nor-1alpha,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells. J Steroid Biochem Mol Biol 127: 269-275.
198. Jaruga E, Salvioli S, Dobrucki J, Chrul S, Bandorowicz-Pikula J, et al. (1998) Apoptosis-like, reversible changes in plasma membrane asymmetry and permeability, and transient modifications in mitochondrial membrane potential induced by curcumin in rat thymocytes. FEBS Lett 433: 287-293.
199. Tsui KH, Chung LC, Feng TH, Chang PL, Juang HH (2012) Upregulation of prostate-derived Ets factor by luteolin causes inhibition of cell proliferation and cell invasion in prostate carcinoma cells. Int J Cancer 130: 2812-2823.
200. Ohyama Y, Ozono K, Uchida M, Shinki T, Kato S, et al. (1994) Identification of a vitamin D-responsive element in the 5'-flanking region of the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J Biol Chem 269: 10545-10550.
201. Kerry DM, Dwivedi PP, Hahn CN, Morris HA, Omdahl JL, et al. (1996) Transcriptional synergism between vitamin D-responsive elements in the rat 25-hydroxyvitamin D3 24-hydroxylase (CYP24) promoter. J Biol Chem 271: 29715-29721.
202. Lopes N, Sousa B, Martins D, Gomes M, Vieira D, et al. (2010) Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions. BMC Cancer 10: 483.
203. Chen WY, Bertone-Johnson ER, Hunter DJ, Willett WC, Hankinson SE (2005) Associations between polymorphisms in the vitamin D receptor and breast cancer risk. Cancer Epidemiol Biomarkers Prev 14: 2335-2339.
204. Uitterlinden AG, Fang Y, van Meurs JB, van Leeuwen H, Pols HA (2004) Vitamin D receptor gene polymorphisms in relation to Vitamin D related disease states. J Steroid Biochem Mol Biol 89-90: 187-193.
205. Costa JL, Eijk PP, van de Wiel MA, ten Berge D, Schmitt F, et al. (2009) Anti-proliferative action of vitamin D in MCF7 is still active after siRNA-VDR knock-down. BMC Genomics 10: 499.
206. Saito N, Honzawa S, Kittaka A (2006) Recent results on A-ring modification of 1alpha,25-dihydroxyvitamin D3: design and synthesis of VDR-agonists and antagonists with high biological activity. Curr Top Med Chem 6: 1273-1288.
207. Hourai S, Fujishima T, Kittaka A, Suhara Y, Takayama H, et al. (2006) Probing a water channel near the A-ring of receptor-bound 1 alpha,25-dihydroxyvitamin D3 with selected 2 alpha-substituted analogues. J Med Chem 49: 5199-5205.
208. Suhara Y, Nihei KI, Kurihara M, Kittaka A, Yamaguchi K, et al. (2001) Efficient and versatile synthesis of novel 2alpha-substituted 1alpha,25-dihydroxyvitamin D(3) analogues and their docking to vitamin D receptors. J Org Chem 66: 8760-8771.
209. Annalora AJ, Goodin DB, Hong WX, Zhang Q, Johnson EF, et al. (2010) Crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism. J Mol Biol 396: 441-451.
210. Fan FS, Yu WC (1995) 1,25-Dihydroxyvitamin D3 suppresses cell growth, DNA synthesis, and phosphorylation of retinoblastoma protein in a breast cancer cell line. Cancer Invest 13: 280-286.
211. Reed JC (1997) Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 34: 9-19.
212. Narvaez CJ, Welsh J (2001) Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells. J Biol Chem 276: 9101-9107.
213. Janicke RU, Sprengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273: 9357-9360.
214. Karp G (2008) Concepts and experiments. Cell and molecular biology. 5 edition ed. Wiley and Sons: John New Jersey. pp. 653-657.
215. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87: 99-163.
216. Boatright KM, Salvesen GS (2003) Mechanisms of caspase activation. Curr Opin Cell Biol 15: 725-731.
217. Brosseau C, Colston K, Dalgleish AG, Galustian C (2012) The immunomodulatory drug lenalidomide restores a vitamin D sensitive phenotype to the vitamin D resistant breast cancer cell line MDA-MB-231 through inhibition of BCL-2: potential for breast cancer therapeutics. Apoptosis 17: 164-173.
218. Brasch J, Harrison OJ, Honig B, Shapiro L (2012) Thinking outside the cell: how cadherins drive adhesion. Trends Cell Biol 22: 299-310.
219. Frixen UH, Nagamine Y (1993) Stimulation of urokinase-type plasminogen activator expression by blockage of E-cadherin-dependent cell-cell adhesion. Cancer Res 53: 3618-3623.
220. Duffy MJ, O'Grady P, Devaney D, O'Siorain L, Fennelly JJ, et al. (1988) Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report. Cancer 62: 531-533.
221. Duffy MJ, Reilly D, O'Sullivan C, O'Higgins N, Fennelly JJ, et al. (1990) Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 50: 6827-6829.
222. Koli K, Keski-Oja J (2000) 1alpha,25-dihydroxyvitamin D3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells. Cell Growth Differ 11: 221-229.
223. Polette M, Clavel C, Cockett M, Girod de Bentzmann S, Murphy G, et al. (1993) Detection and localization of mRNAs encoding matrix metalloproteinases and their tissue inhibitor in human breast pathology. Invasion Metastasis 13: 31-37.
224. Ueno H, Nakamura H, Inoue M, Imai K, Noguchi M, et al. (1997) Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in human invasive breast carcinomas. Cancer Res 57: 2055-2060.
225. Krishnan AV, Swami S, Peng L, Wang J, Moreno J, et al. (2010) Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy. Endocrinology 151: 32-42.
226. Krishnan AV, Swami S, Feldman D (2010) Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling. J Steroid Biochem Mol Biol 121: 343-348.
227. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62: 10-29.
228. Chiang KC, Yeh CN, Ueng SH, Hsu JT, Yeh TS, et al. (2012) Clinicodemographic aspect of resectable pancreatic cancer and prognostic factors for resectable cancer. World J Surg Oncol 10: 77.
229. Pour PM (1991) The silent killer. Int J Pancreatol 10: 103-104.
230. Trede M, Schwall G, Saeger HD (1990) Survival after pancreatoduodenectomy. 118 consecutive resections without an operative mortality. Ann Surg 211: 447-458.
231. Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, et al. (1997) Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 226: 248-257.
232. Nitecki SS, Sarr MG, Colby TV, van Heerden JA (1995) Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 221: 59-66.
233. Chiang KC, Chen TC (2013) The Anti-cancer Actions of Vitamin D. Anticancer Agents Med Chem 13: 126-139.
234. Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, et al. (2013) Molecular mechanisms of vitamin D action. Calcif Tissue Int 92: 77-98.
235. Chiang KC, Yeh CN, Chen SC, Shen SC, Hsu JT, et al. (2012) MART-10, a New Generation of Vitamin D Analog, Is More Potent than 1alpha,25-Dihydroxyvitamin D(3) in Inhibiting Cell Proliferation and Inducing Apoptosis in ER+ MCF-7 Breast Cancer Cells. Evid Based Complement Alternat Med 2012: 310872.
236. Kittaka A, Yoshida A, Chiang KC, Takano M, Sawada D, et al. (2012) Potent 19-norvitamin D analogs for prostate and liver cancer therapy. Future Med Chem 4: 2049-2065.
237. Zugmaier G, Jager R, Grage B, Gottardis MM, Havemann K, et al. (1996) Growth-inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells. Br J Cancer 73: 1341-1346.
238. Pettersson F, Colston KW, Dalgleish AG (2000) Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro. Br J Cancer 83: 239-245.
239. Persons KS, Eddy VJ, Chadid S, Deoliveira R, Saha AK, et al. (2010) Anti-growth effect of 1,25-dihydroxyvitamin D3-3-bromoacetate alone or in combination with 5-amino-imidazole-4-carboxamide-1-beta-4-ribofuranoside in pancreatic cancer cells. Anticancer Res 30: 1875-1880.
240. Colston KW, James SY, Ofori-Kuragu EA, Binderup L, Grant AG (1997) Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. Br J Cancer 76: 1017-1020.
241. Schwartz GG, Eads D, Naczki C, Northrup S, Chen T, et al. (2008) 19-nor-1 alpha,25-dihydroxyvitamin D2 (paricalcitol) inhibits the proliferation of human pancreatic cancer cells in vitro and in vivo. Cancer Biol Ther 7: 430-436.
242. Evans TR, Colston KW, Lofts FJ, Cunningham D, Anthoney DA, et al. (2002) A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br J Cancer 86: 680-685.
243. Ellsmere J, Mortele K, Sahani D, Maher M, Cantisani V, et al. (2005) Does multidetector-row CT eliminate the role of diagnostic laparoscopy in assessing the resectability of pancreatic head adenocarcinoma? Surg Endosc 19: 369-373.
244. Prokesch RW, Chow LC, Beaulieu CF, Bammer R, Jeffrey RB, Jr. (2002) Isoattenuating pancreatic adenocarcinoma at multi-detector row CT: secondary signs. Radiology 224: 764-768.
245. Saldinger PF, Reilly M, Reynolds K, Raptopoulos V, Chuttani R, et al. (2000) Is CT angiography sufficient for prediction of resectability of periampullary neoplasms? J Gastrointest Surg 4: 233-237; discussion 238-239.
246. Powers JT, Hong S, Mayhew CN, Rogers PM, Knudsen ES, et al. (2004) E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Mol Cancer Res 2: 203-214.
247. Krtolica A, Krucher NA, Ludlow JW (1998) Hypoxia-induced pRB hypophosphorylation results from downregulation of CDK and upregulation of PP1 activities. Oncogene 17: 2295-2304.
248. Harper JW, Elledge SJ (1996) Cdk inhibitors in development and cancer. Curr Opin Genet Dev 6: 56-64.
249. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501-1512.
250. Meeran SM, Katiyar SK (2008) Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci 13: 2191-2202.
251. Geisler J, Lonning PE (2005) Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res 11: 2809-2821.
252. Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, et al. (2002) Aromatase--a brief overview. Annu Rev Physiol 64: 93-127.
253. Blanke CD, Beer TM, Todd K, Mori M, Stone M, et al. (2009) Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer. Invest New Drugs 27: 374-378.
254. Chen TC, Schwartz GG, Burnstein KL, Lokeshwar BL, Holick MF (2000) The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1alpha,25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer. Clin Cancer Res 6: 901-908.
255. Chen TC, Persons K, Liu WW, Chen ML, Holick MF (1995) The antiproliferative and differentiative activities of 1,25-dihydroxyvitamin D3 are potentiated by epidermal growth factor and attenuated by insulin in cultured human keratinocytes. J Invest Dermatol 104: 113-117.
256. Ouyang W, Ma Q, Li J, Zhang D, Liu ZG, et al. (2005) Cyclin D1 induction through IkappaB kinase beta/nuclear factor-kappaB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes. Cancer Res 65: 9287-9293.
257. Vermes I, Haanen C, Reutelingsperger C (2000) Flow cytometry of apoptotic cell death. J Immunol Methods 243: 167-190.
258. Tsui KH, Chung LC, Feng TH, Chang PL, Juang HH (2011) Upregulation of prostate-derived Ets factor by luteolin causes inhibition of cell prolifertation and cell invasion in prostate carcinoma cells. Int J Cancer.