Induction of Differentiation in Cancer Cells by Vitamin D: Recognition and Mechanisms



Current understanding of the vitamin D-induced differentiation of neoplastic cells, which results in the generation of cells that acquire near-normal, mature phenotype is summarized here. The criteria by which differentiation is recognized in each cell type are provided, and only those effects of 1α,25-dihydroxyvitamin D3 (1,25D) on cell proliferation and survival which are associated with the differentiation process are emphasized. The existing knowledge of the signaling pathways that lead to vitamin-D-induced differentiation of colon, breast, prostate, squamous cell carcinoma (SCC), osteosarcoma, and myeloid leukemia cancer cells is outlined. Where known, the distinctions between the different mechanisms of 1,25D-induced differentiation which are cell-type-specific and cell-context-specific are pointed out. A considerable body of evidence suggests that several types of human cancer cells can be suitable candidates for chemoprevention or differentiation therapy with vitamin D. However, further studies of the underlying mechanisms are needed to gain further insights on how to improve the therapeutic approaches that incorporate vitamin D derivatives.


Prostate Cancer Cell HL60 Cell Acute Myeloid Leukemia Cell Keratinocyte Differentiation Epidermal Growth Factor Receptor mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Serine/threonine-specific protein kinase B

Alk Pase

Alkaline phosphatase


Acute myeloid leukemia


Activating protein 1


Adenomatous polyposis coli


Acute promyelocytic leukemia


Androgen receptor


All-trans retinoic acid


Bone morphogenetic protein


Calcium-sensing surface receptor


Cyclin-dependent kinase 5


CCAAT/enhancer binding protein




1α,25-Dihydroxyvitamin D3




Epidermal growth factor receptor


Early growth response protein 1


Early progenitor


Estrogen receptor


Extracellular-signal regulated kinase


Flow Cytometry


Growth factor


Growth factor receptor


Human osteocalcin


Human osteopontin


IGF binding protein-5


Insulin-like growth factor binding protein-3


Inositol triphosphate


Jun N-terminal kinase


Kruppel-like factor 4


Kinase suppressor of Ras-1




Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry


Mitogen activated protein kinase


Monocyte-specific esterase (“non-specific” esterase)


Nitroblue tetrazolium


“Cyclin-like” neuronal Cdk5 activator


Nuclear receptor


Nonspecific esterase






Ribosomal s6 kinase (MAPK-activated protein kinase-1)


Phosphatidylinositol 3-kinase


Phosphatidylinositol 3, 4, 5-triphosphate


Protein kinase C


Phospholipase C gamma-1


Retinoblastoma protein


Prostate specific antigen


Retinoic acid receptor


Reactive oxygen species


Retinoid X receptor alpha


Squamous cell carcinoma


Specificity protein 1


T-cell transcription factor 4


Wingless-related MMTV integration site


Vitamin D receptor


Vitamin D3 response element



We thank Drs. Michael Danilenko, David Goldberg, and Ewa Marcinkowska for comments on the manuscript, and Ms. Vivienne Lowe for expert secretarial assistance. The author’s experimental work was supported by grants from the National Cancer Institute RO1-CA 44722–18 and RO1-CA 117942–01, and from the Polish Ministry of Science and Higher Education, grant No. 2622/P01/2006/31.


  1. 1.
    Smithers DW (1969) Maturation in human tumours. Lancet 2:949–952PubMedGoogle Scholar
  2. 2.
    Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA (2004) Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia 6:838–845PubMedGoogle Scholar
  3. 3.
    Chen SJ, Zhu YJ, Tong JH, Dong S, Huang W, Chen Y, Xiang WM, Zhang L, Li XS, Qian GQ (1991) Rearrangements in the second intron of the RARalfa gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation. Blood 78:2696–2701PubMedGoogle Scholar
  4. 4.
    Degos L, Wang ZY (2001) All trans retinoic acid in acute promyelocytic leukemia. Oncogene 20:7140–7145PubMedGoogle Scholar
  5. 5.
    Schlenk RF, Frohling S, Hartmann F, Fischer JT, Glasmacher A, del Valle F, Grimminger W, Gotze K, Waterhouse C, Schoch R, Pralle H, Mergenthaler HG, Hensel M, Koller E, Kirchen H, Preiss J, Salwender H, Biedermann HG, Kremers S, Griesinger F, Benner A, Addamo B, Dohner K, Haas R, Dohner H (2004) Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia 18:1798–1803PubMedGoogle Scholar
  6. 6.
    Camerini T, Mariani L, De Palo G, Marubini E, Di Mauro MG, Decensi A, Costa A, Veronesi U (2001) Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 19:1664–1670PubMedGoogle Scholar
  7. 7.
    Jung SJ, Lee YY, Pakkala S, de Vos S, Elstner E, Norman AW, Green J, Uskokovic M, Koeffler HP (1994) 1, 25(OH)2–16ene-vitamin D3 is a potent antileukemic agent with low potential to cause hypercalcemia. Leuk Res 18:453–463PubMedGoogle Scholar
  8. 8.
    Jones G (2008) Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 88:582S–586SPubMedGoogle Scholar
  9. 9.
    Bouillon R, Okamura WH, Norman AW (1995) Structure-function relationships in the ­vitamin D endocrine system. Endocr Rev 16:200–257PubMedGoogle Scholar
  10. 10.
    Ji Y, Wang X, Donnelly RJ, Uskokovic MR, Studzinski GP (2002) Signaling of monocytic differentiation by a non-hypercalcemic analog of vitamin D3, 1, 25(OH)2–5, 6 trans-16-ene-vitamin D3, involves nuclear vitamin D receptor (nVDR) and non-nVDR-mediated pathways. J Cell Physiol 191:198–207PubMedGoogle Scholar
  11. 11.
    Collins ED, Bishop JE, Bula CM, Acevedo A, Okamura WH, Norman AW (2005) Effect of 25-hydroxyl group orientation on biological activity and binding to the 1alpha, 25-dihydroxy vitamin D3 receptor. J Steroid Biochem Mol Biol 94:279–288PubMedGoogle Scholar
  12. 12.
    Aparna R, Subhashini J, Roy KR, Reddy GS, Robinson M, Uskokovic MR, Venkateswara Reddy G, Reddanna P (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 104:1832–1842PubMedGoogle Scholar
  13. 13.
    Danilenko M, Wang X, Studzinski GP (2001) Carnosic acid and promotion of monocytic differentiation of HL60-G cells initiated by other agents. J Natl Cancer Inst 93:1224–1233PubMedGoogle Scholar
  14. 14.
    Danilenko M, Wang Q, Wang X, Levy J, Sharoni Y, Studzinski GP (2003) Carnosic acid potentiates the antioxidant and prodifferentiation effects of 1alpha, 25-dihydroxyvitamin D3 in leukemia cells but does not promote elevation of basal levels of intracellular calcium. Cancer Res 63:1325–1332PubMedGoogle Scholar
  15. 15.
    Danilenko M, Studzinski GP (2004) Enhancement by other compounds of the anti-cancer activity of vitamin D3 and its analogs. Exp Cell Res 298:339–358PubMedGoogle Scholar
  16. 16.
    Coffman FD, Studzinski GP (1999) Differentiation-related mechanisms which suppress DNA replication. Exp Cell Res 248:58–73PubMedGoogle Scholar
  17. 17.
    Harrison LE, Wang QM, Studzinski GP (1999) Butyrate-induced G2/M block in CaCo-2 colon cancer cells is associated with decreased p34cdc2 activity. Proc Soc Exp Biol Med 222:150–156PubMedGoogle Scholar
  18. 18.
    Harrison LE, Wang QM, Studzinski GP (1999) 1, 25-dihydroxyvitamin D3-induced retardation of the G(2)/M traverse is associated with decreased levels of p34(cdc2) in HL60 cells. J Cell Biochem 75:226–234PubMedGoogle Scholar
  19. 19.
    Wang QM, Studzinski GP, Chen F, Coffman FD, Harrison LE (2000) p53/56(lyn) antisense shifts the 1, 25-dihydroxyvitamin D3-induced G1/S block in HL60 cells to S phase. J Cell Physiol 183:238–246PubMedGoogle Scholar
  20. 20.
    Welsh J, Simboli-Campbell M, Narvaez CJ, Tenniswood M (1995) Role of apoptosis in the growth inhibitory effects of vitamin D in MCF-7 cells. Adv Exp Med Biol 375:45–52PubMedGoogle Scholar
  21. 21.
    Li F, Ling X, Huang H, Brattain L, Apontes P, Wu J, Binderup L, Brattain MG (2005) Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines. Oncogene 24:1385–1395PubMedGoogle Scholar
  22. 22.
    Myrthue A, Rademacher BL, Pittsenbarger J, Kutyba-Brooks B, Gantner M, Qian DZ, Beer TM (2008) The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells. Clin Cancer Res 14:3562–3570PubMedGoogle Scholar
  23. 23.
    Wang X, Studzinski GP (1997) Antiapoptotic action of 1, 25-dihydroxyvitamin D3 is associated with increased mitochondrial MCL-1 and RAF-1 proteins and reduced release of ­cytochrome c. Exp Cell Res 235:210–217PubMedGoogle Scholar
  24. 24.
    Wang X, Patel R, Studzinski GP (2008) hKSR-2, a vitamin D-regulated gene, inhibits apoptosis in arabinocytosine-treated HL60 leukemia cells. Mol Cancer Ther 7:2798–2806PubMedGoogle Scholar
  25. 25.
    Helander HF (1975) Enzyme patterns and protein absorption in rat colon during development. Acta Anat (Basel) 91:330–349Google Scholar
  26. 26.
    Ono K (1976) Alkaline phosphatase activity of the large intestinal principal cells in postnatal developing rats. Acta Histochem 57:312–319PubMedGoogle Scholar
  27. 27.
    Chen A, Davis BH, Bissonnette M, Scaglione-Sewell B, Brasitus TA (1999) 1,25-Dihydroxyvitamin D3 stimulates activator protein-1-dependent CaCo-2 cell differentiation. J Biol Chem 274:35505–35513PubMedGoogle Scholar
  28. 28.
    Marvin-Guy LF, Duncan P, Wagniere S, Antille N, Porta N, Affolter M, Kussmann M (2008) Rapid identification of differentiation markers from whole epithelial cells by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry and statistical analysis. Rapid Commun Mass Spectrom 22:1099–1108PubMedGoogle Scholar
  29. 29.
    Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M, Munoz A (2001) Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 154:369–387PubMedGoogle Scholar
  30. 30.
    Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED (1989) Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 2:1176–1178PubMedGoogle Scholar
  31. 31.
    Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC (2006) Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 98:451–459PubMedGoogle Scholar
  32. 32.
    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 11:77–84PubMedGoogle Scholar
  33. 33.
    Belleli A, Shany S, Levy J, Guberman R, Lamprecht SA (1992) A protective role of 1, 25-dihydroxyvitamin D3 in chemically induced rat colon carcinogenesis. Carcinogenesis 13:2293–2298PubMedGoogle Scholar
  34. 34.
    Shabahang M, Buras RR, Davoodi F, Schumaker LM, Nauta RJ, Evans SR (1993) 1, 25-Dihydroxyvitamin D3 receptor as a marker of human colon carcinoma cell line differentiation and growth inhibition. Cancer Res 53:3712–3718PubMedGoogle Scholar
  35. 35.
    Vandewalle B, Adenis A, Hornez L, Revillion F, Lefebvre J (1994) 1, 25-dihydroxyvitamin D3 receptors in normal and malignant human colorectal tissues. Cancer Lett 86:67–73PubMedGoogle Scholar
  36. 36.
    Sheinin Y, Kaserer K, Wrba F, Wenzl E, Kriwanek S, Peterlik M, Cross HS (2000) In situ mRNA hybridization analysis and immunolocalization of the vitamin D receptor in normal and carcinomatous human colonic mucosa: relation to epidermal growth factor receptor expression. Virchows Arch 437:501–507PubMedGoogle Scholar
  37. 37.
    Cross HS, Bareis P, Hofer H, Bischof MG, Bajna E, Kriwanek S, Bonner E, Peterlik M (2001) 25-Hydroxyvitamin D3–1alpha-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis. Steroids 66:287–292PubMedGoogle Scholar
  38. 38.
    Qi X, Pramanik R, Wang J, Schultz RM, Maitra RK, Han J, DeLuca HF, Chen G (2002) The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun/AP-1 and sensitize human breast cancer cells to vitamin D3-induced growth inhibition. J Biol Chem 277:25884–25892PubMedGoogle Scholar
  39. 39.
    Wiese RJ, Uhland-Smith A, Ross TK, Prahl JM, DeLuca HF (1992) Up-regulation of the vitamin D receptor in response to 1, 25-dihydroxyvitamin D3 results from ligand-induced stabilization. J Biol Chem 267:20082–20086PubMedGoogle Scholar
  40. 40.
    Alrefai WA, Scaglione-Sewell B, Tyagi S, Wartman L, Brasitus TA, Ramaswamy K, Dudeja PK (2001) Differential regulation of the expression of Na+/H+ exchanger isoform NHE3 by PKC-alpha in CaCo-2 cells. Am J Physiol Cell Physiol 281:C1551–C1558PubMedGoogle Scholar
  41. 41.
    Wali RK, Baum CL, Sitrin MD, Brasitus TA (1990) 1, 25(OH)2 vitamin D3 stimulates membrane phosphoinositide turnover, activates protein kinase C, and increases cytosolic calcium in rat colonic epithelium. J Clin Invest 85:1296–1303PubMedGoogle Scholar
  42. 42.
    Gaschott T, Werz O, Steinmeyer A, Steinhilber D, Stein J (2001) Butyrate-induced differentiation of CaCo-2 cells is mediated by vitamin D receptor. Biochem Biophys Res Commun 288:690–696PubMedGoogle Scholar
  43. 43.
    Cui M, Klopot A, Jiang Y, Fleet JC (2009) The effect of differentiation on 1, 25 dihydroxyvitamin D-mediated gene expression in the enterocyte-like cell line, CaCo-2. J Cell Physiol 218(1):113–121PubMedGoogle Scholar
  44. 44.
    Easwaran V, Pishvaian M, Salimuddin, Byers S (1999) Cross-regulation of beta-catenin-LEF/TCF and retinoid signaling pathways. Curr Biol 9:1415–1418PubMedGoogle Scholar
  45. 45.
    Shah S, Islam MN, Dakshanamurthy S, Rizvi I, Rao M, Herrell R, Zinser G, Valrance M, Aranda A, Moras D, Norman A, Welsh J, Byers SW (2006) The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell 21:799–809PubMedGoogle Scholar
  46. 46.
    Larriba MJ, Valle N, Palmer HG, Ordonez-Moran P, Alvarez-Diaz S, Becker KF, Gamallo C, de Herreros AG, Gonzalez-Sancho JM, Munoz A (2007) The inhibition of Wnt/beta-catenin signalling by 1alpha, 25-dihydroxyvitamin D3 is abrogated by Snail1 in human colon cancer cells. Endocr Relat Cancer 14:141–151PubMedGoogle Scholar
  47. 47.
    Pendas-Franco N, Garcia JM, Pena C, Valle N, Palmer HG, Heinaniemi M, Carlberg C, Jimenez B, Bonilla F, Munoz A, Gonzalez-Sancho JM (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 27:4467–4477PubMedGoogle Scholar
  48. 48.
    Gumbiner BM (1996) Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84:345–357PubMedGoogle Scholar
  49. 49.
    Wilson AJ, Velcich A, Arango D, Kurland AR, Shenoy SM, Pezo RC, Levsky JM, Singer RH, Augenlicht LH (2002) Novel detection and differential utilization of a c-myc transcriptional block in colon cancer chemoprevention. Cancer Res 62:6006–6010PubMedGoogle Scholar
  50. 50.
    Huang YC, Chen JY, Hung WC (2004) Vitamin D3 receptor/Sp1 complex is required for the induction of p27Kip1 expression by vitamin D3. Oncogene 23:4856–4861PubMedGoogle Scholar
  51. 51.
    Zinser GM, Suckow M, Welsh J (2005) Vitamin D receptor (VDR) ablation alters carcinogen-induced tumorigenesis in mammary gland, epidermis and lymphoid tissues. J Steroid Biochem Mol Biol 97:153–164PubMedGoogle Scholar
  52. 52.
    Welsh J (2004) Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr 80:1721S–1724SPubMedGoogle Scholar
  53. 53.
    Escaleira MT, Brentani MM (1999) Vitamin D3 receptor (VDR) expression in HC-11 mammary cells: regulation by growth-modulatory agents, differentiation, and Ha-Ras transformation. Breast Cancer Res Treat 54:123–133PubMedGoogle Scholar
  54. 54.
    Pendas-Franco N, Gonzalez-Sancho JM, Suarez Y, Aguilera O, Steinmeyer A, Gamallo C, Berciano MT, Lafarga M, Munoz A (2007) Vitamin D regulates the phenotype of human breast cancer cells. Differentiation 75:193–207PubMedGoogle Scholar
  55. 55.
    Agadir A, Lazzaro G, Zheng Y, Zhang XK, Mehta R (1999) Resistance of HBL100 human breast epithelial cells to vitamin D action. Carcinogenesis 20:577–582PubMedGoogle Scholar
  56. 56.
    Valrance ME, Brunet AH, Welsh J (2007) Vitamin D receptor-dependent inhibition of mammary tumor growth by EB1089 and ultraviolet radiation in vivo. Endocrinology 148:4887–4894PubMedGoogle Scholar
  57. 57.
    Byrne B, Welsh J (2007) Identification of novel mediators of Vitamin D signaling and 1, 25(OH)2D3 resistance in mammary cells. J Steroid Biochem Mol Biol 103:703–707PubMedGoogle Scholar
  58. 58.
    Wang Q, Lee D, Sysounthone V, Chandraratna RAS, Christakos S, Korah R, Wieder R (2001) 1, 25-dihydroxyvitamin D3 and retinoic acid analogues induce differentiation in breast cancer cells with function- and cell-specific additive effects. Breast Cancer Res Treat 67:157–168PubMedGoogle Scholar
  59. 59.
    Simboli-Campbell M, Narvaez CJ, van Weelden K, Tenniswood M, Welsh J (1997) Comparative effects of 1, 25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells. Breast Cancer Res Treat 42:31–41PubMedGoogle Scholar
  60. 60.
    Byrne BM, Welsh J (2005) Altered thioredoxin subcellular localization and redox status in MCF-7 cells following 1, 25-dihydroxyvitamin D3 treatment. J Steroid Biochem Mol Biol 97:57–64PubMedGoogle Scholar
  61. 61.
    Li QP, Qi X, Pramanik R, Pohl NM, Loesch M, Chen G (2007) Stress-induced c-Jun-dependent Vitamin D receptor (VDR) activation dissects the non-classical VDR pathway from the classical VDR activity. J Biol Chem 282:1544–1551PubMedGoogle Scholar
  62. 62.
    McGaffin KR, Acktinson LE, Chrysogelos SA (2004) Growth and EGFR regulation in breast cancer cells by vitamin D and retinoid compounds. Breast Cancer Res Treat 86:55–73PubMedGoogle Scholar
  63. 63.
    McGaffin KR, Chrysogelos SA (2005) Identification and characterization of a response ­element in the EGFR promoter that mediates transcriptional repression by 1, 25-dihydroxyvitamin D3 in breast cancer cells. J Mol Endocrinol 35:117–133PubMedGoogle Scholar
  64. 64.
    Campbell MJ, Gombart AF, Kwok SH, Park S, Koeffler HP (2000) The anti-proliferative effects of 1alpha, 25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression. Oncogene 19:5091–5097PubMedGoogle Scholar
  65. 65.
    Lazzaro G, Agadir A, Qing W, Poria M, Mehta RR, Moriarty RM, Das Gupta TK, Zhang XK, Mehta RG (2000) Induction of differentiation by 1alpha-hydroxyvitamin D5 in T47D human breast cancer cells and its interaction with vitamin D receptors. Eur J Cancer 36:780–786PubMedGoogle Scholar
  66. 66.
    Peng X, Jhaveri P, Hussain-Hakimjee EA, Mehta RG (2007) Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1alpha-hydroxyvitamin D5. Carcinogenesis 28:1000–2007PubMedGoogle Scholar
  67. 67.
    Campbell MJ, Reddy GS, Koeffler HP (1997) Vitamin D3 analogs and their 24-oxo metabolites equally inhibit clonal proliferation of a variety of cancer cells but have differing molecular effects. J Cell Biochem 66:413–425PubMedGoogle Scholar
  68. 68.
    Getzenberg RH, Light BW, Lapco PE, Konety BR, Nangia AK, Acierno JS, Dhir R, Shurin Z, Day RS, Trump DL, Johnson CS (1997) Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology 50:999–1006PubMedGoogle Scholar
  69. 69.
    Zhao XY, Feldman D (2001) The role of vitamin D in prostate cancer. Steroids 66:293–300PubMedGoogle Scholar
  70. 70.
    Krishnan AV, Peehl DM, Feldman D (2003) Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression. J Cell Biochem 88:363–71PubMedGoogle Scholar
  71. 71.
    Beer TM, Garzotto M, Park B, Mori M, Myrthue A, Janeba N, Sauer D, Eilers K (2006) Effect of calcitriol on prostate-specific antigen in vitro and in humans. Clin Cancer Res 12:2812–2816PubMedGoogle Scholar
  72. 72.
    Reiter W (1999) The clinical value of the Enzymun-Test for total and free PSA – a multicentre evaluation. Anticancer Res 19:5559–5562PubMedGoogle Scholar
  73. 73.
    Konety BR, Schwartz GG, Acierno JS Jr, Becich MJ, Getzenberg RH (1996) The role of vitamin D in normal prostate growth and differentiation. Cell Growth Differ 7:1563–1570PubMedGoogle Scholar
  74. 74.
    Floryk D, Tollaksen SL, Giometti CS, Huberman E (2004) Differentiation of human prostate cancer PC-3 cells induced by inhibitors of inosine 5′-monophosphate dehydrogenase. Cancer Res 64:9049–9056PubMedGoogle Scholar
  75. 75.
    Campbell MJ, Elstner E, Holden S, Uskokovic M, Koeffler HP (1997) Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. J Mol Endocrinol 19:15–27PubMedGoogle Scholar
  76. 76.
    Ortel B, Sharlin D, ÓDonnell D, Sinha AK, Maytin EV, Hasan T (2002) Differentiation enhances aminolevulinic acid-dependent photodynamic treatment of LNCaP prostate cancer cells. Br J Cancer 87:1321–1327PubMedGoogle Scholar
  77. 77.
    Krishnan AV, Shinghal R, Raghavachari N, Brooks JD, Peehl DM, Feldman D (2004) Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays. Prostate 59:243–251PubMedGoogle Scholar
  78. 78.
    Boyle BJ, Zhao XY, Cohen P, Feldman D (2001) Insulin-like growth factor binding protein-3 mediates 1 alpha, 25-dihydroxyvitamin D3 growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1. J Urol 165:1319–1324PubMedGoogle Scholar
  79. 79.
    Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA, Thompson DD (1998) Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J Biol Chem 273:13760–13767PubMedGoogle Scholar
  80. 80.
    Zhao XY, Ly LH, Peehl DM, Feldman D (1999) Induction of androgen receptor by 1alpha, 25-dihydroxyvitamin D3 and 9-cis retinoic acid in LNCaP human prostate cancer cells. Endocrinology 140:1205–1212PubMedGoogle Scholar
  81. 81.
    Zhao XY, Peehl DM, Navone NM, Feldman D (2000) 1alpha, 25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms. Endocrinology 141:2548–2556PubMedGoogle Scholar
  82. 82.
    Tuohimaa P, Lyakhovich A, Aksenov N, Pennanen P, Syvala H, Lou YR, Ahonen M, Hasan T, Pasanen P, Blauer M, Manninen T, Miettinen S, Vilja P, Ylikomi T (2001) Vitamin D and prostate cancer. J Steroid Biochem Mol Biol 76:125–134PubMedGoogle Scholar
  83. 83.
    Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D (2005) Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res 65:7917–7925PubMedGoogle Scholar
  84. 84.
    Cussenot O, Villette JM, Cochand-Priollet B, Berthon P (1998) Evaluation and clinical value of neuroendocrine differentiation in human prostatic tumors. Prostate Suppl 8:43–51PubMedGoogle Scholar
  85. 85.
    Xiao W, Hodge DR, Wang L, Yang X, Zhang X, Farrar WL (2004) Co-operative functions between nuclear factors NFkB and CCAT/enhancer-binding protein-beta (C/EBP-beta) regulate the IL-6 promoter in autocrine human prostate cancer cells. Prostate 61:354–370PubMedGoogle Scholar
  86. 86.
    Mori R, Xiong S, Wang Q, Tarabolous C, Shimada H, Panteris E, Danenberg KD, Danenberg PV, Pinski JK (2009) Gene profiling and pathway analysis of neuroendocrine transdifferentiated prostate cancer cells. Prostate 69:12–23PubMedGoogle Scholar
  87. 87.
    Marcinkowska E, Garay E, Gocek E, Chrobak A, Wang X, Studzinski GP (2006) Regulation of C/EBPbeta isoforms by MAPK pathways in HL60 cells induced to differentiate by 1, 25-dihydroxyvitamin D3. Exp Cell Res 312:2054–2065PubMedGoogle Scholar
  88. 88.
    Abban G, Yildirim NB, Jetten AM (2008) Regulation of the vitamin D receptor and cornifin beta expression in vaginal epithelium of the rats through vitamin D3. Eur J Histochem 52:107–114PubMedGoogle Scholar
  89. 89.
    White JH (2004) Profiling 1, 25-dihydroxyvitamin D3-regulated gene expression by ­microarray analysis. J Steroid Biochem Mol Biol 89–90:239–244PubMedGoogle Scholar
  90. 90.
    Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ, Schalken JA (2000) Cadherin switching in human prostate cancer progression. Cancer Res 60:3650–3654PubMedGoogle Scholar
  91. 91.
    Bikle DD, Ng D, Tu CL, Oda Y, Xie Z (2001) Calcium- and vitamin D-regulated keratinocyte differentiation. Mol Cell Endocrinol 177:161–171PubMedGoogle Scholar
  92. 92.
    Xie Z, Bikle DD (2007) The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and human keratinocyte differentiation. J Biol Chem 282:8695–8703PubMedGoogle Scholar
  93. 93.
    Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA, Schlessinger J (1998) Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. Embo J 17:414–422PubMedGoogle Scholar
  94. 94.
    Xie Z, Singleton PA, Bourguignon LY, Bikle DD (2005) Calcium-induced human keratinocyte differentiation requires src- and fyn-mediated phosphatidylinositol 3-kinase-dependent activation of phospholipase C-gamma1. Mol Biol Cell 16:3236–3246PubMedGoogle Scholar
  95. 95.
    Bikle DD, Oda Y, Xie Z (2005) Vitamin D and skin cancer: a problem in gene regulation. J Steroid Biochem Mol Biol 97:83–91PubMedGoogle Scholar
  96. 96.
    Lehen’kyi V, Beck B, Polakowska R, Charveron M, Bordat P, Skryma R, Prevarskaya N (2007) TRPV6 is a Ca2+ entry channel essential for Ca2+-induced differentiation of human keratinocytes. J Biol Chem 282:22582–22591PubMedGoogle Scholar
  97. 97.
    Johansen C, Iversen L, Ryborg A, Kragballe K (2000) 1alpha, 25-dihydroxyvitamin D3 induced differentiation of cultured human keratinocytes is accompanied by a PKC-independent regulation of AP-1 DNA binding activity. J Invest Dermatol 114:1174–1179PubMedGoogle Scholar
  98. 98.
    Takahashi H, Ibe M, Honma M, Ishida-Yamamoto A, Hashimoto Y, Iizuka H (2003) 1, 25-dihydroxyvitamin D3 increases human cystatin A expression by inhibiting the Raf-1/MEK1/ERK signaling pathway of keratinocytes. Arch Dermatol Res 295:80–87PubMedGoogle Scholar
  99. 99.
    Takahashi H, Honma M, Ishida-Yamamoto A, Namikawa K, Kiyama H, Iizuka H (2001) Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. J Biol Chem 276:36632–36638PubMedGoogle Scholar
  100. 100.
    Lippens S, Kockx M, Denecker G, Knaapen M, Verheyen A, Christiaen R, Tschachler E, Vandenabeele P, Declercq W (2004) Vitamin D3 induces caspase-14 expression in psoriatic lesions and enhances caspase-14 processing in organotypic skin cultures. Am J Pathol 165:833–841PubMedGoogle Scholar
  101. 101.
    Manggau M, Kim DS, Ruwisch L, Vogler R, Korting HC, Schafer-Korting M, Kleuser B (2001) 1alpha, 25-dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate. J Invest Dermatol 117:1241–1249PubMedGoogle Scholar
  102. 102.
    Lu J, Goldstein KM, Chen P, Huang S, Gelbert LM, Nagpal S (2005) Transcriptional profiling of keratinocytes reveals a vitamin D-regulated epidermal differentiation network. J Invest Dermatol 124:778–785PubMedGoogle Scholar
  103. 103.
    Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H, Hirai H, Katz JP, Haspel RL, Gray S, Akashi K, Segre J, Kaestner KH, Tenen DG, Jain MK (2007) The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. Embo J 26:4138–4148PubMedGoogle Scholar
  104. 104.
    Autieri MV (2008) Kruppel-like factor 4: transcriptional regulator of proliferation, or inflammation, or differentiation, or all three? Circ Res 102:1455–1457PubMedGoogle Scholar
  105. 105.
    Alder JK, Georgantas RW 3rd, Hildreth RL, Kaplan IM, Morisot S, Yu X, McDevitt M, Civin CI (2008) Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol 180:5645–5652PubMedGoogle Scholar
  106. 106.
    Dai X, Sayama K, Shirakata Y, Tokumaru S, Yang L, Tohyama M, Hirakawa S, Hanakawa Y, Hashimoto K (2008) PPAR gamma is an important transcription factor in 1 alpha, 25-dihydroxyvitamin D3-induced involucrin expression. J Dermatol Sci 50:53–60PubMedGoogle Scholar
  107. 107.
    Bikle DD, Pillai S, Gee E (1991) Squamous carcinoma cell lines produce 1, 25 dihydroxyvitamin D, but fail to respond to its prodifferentiating effect. J Invest Dermatol 97:435–441PubMedGoogle Scholar
  108. 108.
    Solomon C, White JH, Kremer R (1999) Mitogen-activated protein kinase inhibits 1, 25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor alpha. J Clin Invest 103:1729–1735PubMedGoogle Scholar
  109. 109.
    McGuire TF, Trump DL, Johnson CS (2001) Vitamin D3-induced apoptosis of murine squamous cell carcinoma cells. Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1. J Biol Chem 276:26365–26373PubMedGoogle Scholar
  110. 110.
    Ma Y, Yu WD, Kong RX, Trump DL, Johnson CS (2006) Role of nongenomic activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase 1/2 pathways in 1,25D3-mediated apoptosis in squamous cell carcinoma cells. Cancer Res 66:8131–8138PubMedGoogle Scholar
  111. 111.
    Xie Z, Bikle DD (1998) Differential regulation of vitamin D responsive elements in normal and transformed keratinocytes. J Invest Dermatol 110:730–733PubMedGoogle Scholar
  112. 112.
    Goltzman D, White J, Kremer R (2001) Studies of the effects of 1, 25-dihydroxyvitamin D on skeletal and calcium homeostasis and on inhibition of tumor cell growth. J Steroid Biochem Mol Biol 76:43–47PubMedGoogle Scholar
  113. 113.
    Oda Y, Sihlbom C, Chalkley RJ, Huang L, Rachez C, Chang CP, Burlingame AL, Freedman LP, Bikle DD (2003) Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation. Mol Endocrinol 17:2329–2339PubMedGoogle Scholar
  114. 114.
    Tokuumi Y (1995) Correlation between the concentration of 1, 25 alpha dihydroxyvitamin D3 receptors and growth inhibition, and differentiation of human osteosarcoma cells induced by vitamin D3. Nippon Seikeigeka Gakkai Zasshi 69:181–190PubMedGoogle Scholar
  115. 115.
    Van Auken M, Buckley D, Ray R, Holick MF, Baran DT (1996) Effects of the vitamin D3 analog 1 alpha, 25-dihydroxyvitamin D3–3 beta-bromoacetate on rat osteosarcoma cells: comparison with 1 alpha, 25-dihydroxyvitamin D3. J Cell Biochem 63:302–310PubMedGoogle Scholar
  116. 116.
    Harris SA, Enger RJ, Riggs BL, Spelsberg TC (1995) Development and characterization of a conditionally immortalized human fetal osteoblastic cell line. J Bone Miner Res 10:178–86PubMedGoogle Scholar
  117. 117.
    Vertino AM, Bula CM, Chen JR, Almeida M, Han L, Bellido T, Kousteni S, Norman AW, Manolagas SC (2005) Nongenotropic, anti-apoptotic signaling of 1alpha, 25(OH)2-vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes. Mediation by Src, phosphatidylinositol 3-, and JNK kinases. J Biol Chem 280:14130–14137PubMedGoogle Scholar
  118. 118.
    Cordero JB, Cozzolino M, Lu Y, Vidal M, Slatopolsky E, Stahl PD, Barbieri MA, Dusso A (2002) 1, 25-Dihydroxyvitamin D down-regulates cell membrane growth- and nuclear growth-promoting signals by the epidermal growth factor receptor. J Biol Chem 277:38965–38971PubMedGoogle Scholar
  119. 119.
    Gonzalez EA, Disthabanchong S, Kowalewski R, Martin KJ (2002) Mechanisms of the regulation of EGF receptor gene expression by calcitriol and parathyroid hormone in UMR 106–01 cells. Kidney Int 61:1627–1634PubMedGoogle Scholar
  120. 120.
    Schedlich LJ, Muthukaruppan A, ÓHan MK, Baxter RC (2007) Insulin-like growth factor binding protein-5 interacts with the vitamin D receptor and modulates the vitamin D response in osteoblasts. Mol Endocrinol 21:2378–2390PubMedGoogle Scholar
  121. 121.
    Lu X, Farmer P, Rubin J, Nanes MS (2004) Integration of the NFkappaB p65 subunit into the vitamin D receptor transcriptional complex: identification of p65 domains that inhibit 1, 25-dihydroxyvitamin D3-stimulated transcription. J Cell Biochem 92:833–848PubMedGoogle Scholar
  122. 122.
    Lemire JM, Adams JS, Sakai R, Jordan SC (1984) 1 alpha, 25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 74:657–661PubMedGoogle Scholar
  123. 123.
    Tsoukas CD, Provvedini DM, Manolagas SC (1984) 1, 25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science 224:1438–1440PubMedGoogle Scholar
  124. 124.
    Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, Yoshiki S, Suda T (1981) Differentiation of mouse myeloid leukemia cells induced by 1 alpha, 25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 78:4990–4994PubMedGoogle Scholar
  125. 125.
    Tanaka H, Abe E, Miyaura C, Kuribayashi T, Konno K, Nishii Y, Suda T (1982) 1 alpha, 25-Dihydroxycholecalciferol and a human myeloid leukaemia cell line (HL-60). Biochem J 204:713–719PubMedGoogle Scholar
  126. 126.
    Studzinski GP, Bhandal AK, Brelvi ZS (1985) A system for monocytic differentiation of leukemic cells HL 60 by a short exposure to 1, 25-dihydroxycholecalciferol. Proc Soc Exp Biol Med 179:288–295PubMedGoogle Scholar
  127. 127.
    Munker R, Norman A, Koeffler HP (1986) Vitamin D compounds. Effect on clonal proliferation and differentiation of human myeloid cells. J Clin Invest 78:424–430PubMedGoogle Scholar
  128. 128.
    Brackman D, Lund-Johansen F, Aarskog D (1995) Expression of cell surface antigens during the differentiation of HL-60 cells induced by 1, 25-dihydroxyvitamin D3, retinoic acid and DMSO. Leuk Res 19:57–64PubMedGoogle Scholar
  129. 129.
    Uphoff CC, Drexler HG (2000) Biology of monocyte-specific esterase. Leuk Lymphoma 39:257–270PubMedGoogle Scholar
  130. 130.
    Steiner M, Priel I, Giat J, Levy J, Sharoni Y, Danilenko M (2001) Carnosic acid inhibits proliferation and augments differentiation of human leukemic cells induced by 1, 25-dihydroxyvitamin D3 and retinoic acid. Nutr Cancer 41:135–144PubMedGoogle Scholar
  131. 131.
    Sharabani H, Izumchenko E, Wang Q, Kreinin R, Steiner M, Barvish Z, Kafka M, Sharoni Y, Levy J, Uskokovic M, Studzinski GP, Danilenko M (2006) Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia. Int J Cancer 118:3012–3021PubMedGoogle Scholar
  132. 132.
    Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431–1433PubMedGoogle Scholar
  133. 133.
    Hickstein DD, Ozols J, Williams SA, Baenziger JU, Locksley RM, Roth GJ (1987) Isolation and characterization of the receptor on human neutrophils that mediates cellular adherence. J Biol Chem 262:5576–5580PubMedGoogle Scholar
  134. 134.
    Studzinski GP, Rathod B, Wang QM, Rao J, Zhang F (1997) Uncoupling of cell cycle arrest from the expression of monocytic differentiation markers in HL60 cell variants. Exp Cell Res 232:376–387PubMedGoogle Scholar
  135. 135.
    Ji Y, Kutner A, Verstuyf A, Verlinden L, Studzinski GP (2002) Derivatives of vitamins D2 and D3 activate three MAPK pathways and upregulate pRb expression in differentiating HL60 cells. Cell Cycle 1:410–415PubMedGoogle Scholar
  136. 136.
    Sikora E, Grassilli E, Bellesia E, Troiano L, Franceschi C (1993) Studies of the relationship between cell proliferation and cell death. III. AP-1 DNA-binding activity during concanavalin A-induced proliferation or dexamethasone-induced apoptosis of rat thymocytes. Biochem Biophys Res Commun 192:386–391PubMedGoogle Scholar
  137. 137.
    Hewison M, Dabrowski M, Vadher S, Faulkner L, Cockerill FJ, Brickell PM, ÓRiordan JL, Katz DR (1996) Antisense inhibition of vitamin D receptor expression induces apoptosis in monoblastoid U937 cells. J Immunol 156:4391–4400PubMedGoogle Scholar
  138. 138.
    Marcinkowska E, Chrobak A, Wiedlocha A (2001) Evading apoptosis by calcitriol-differentiated human leukemic HL-60 cells is not mediated by changes in CD95 receptor system but by increased sensitivity of these cells to insulin. Exp Cell Res 270:119–127PubMedGoogle Scholar
  139. 139.
    Zhang Y, Zhang J, Studzinski GP (2006) AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic effect and cell cycle control in differentiating HL60 cells. Cell Cycle 5:447–451PubMedGoogle Scholar
  140. 140.
    Wang X, Studzinski GP (2006) The requirement for and changing composition of the activating protein-1 transcription factor during differentiation of human leukemia HL60 cells induced by 1, 25-dihydroxyvitamin D3. Cancer Res 66:4402–4409PubMedGoogle Scholar
  141. 141.
    Nakagawa K, Kurobe M, Konno K, Fujishima T, Takayama H, Okano T (2000) Structure-specific control of differentiation and apoptosis of human promyelocytic leukemia (HL-60) cells by A-ring diastereomers of 2-methyl-1alpha, 25-dihydroxyvitamin D3 and its 20-epimer. Biochem Pharmacol 60:1937–1947PubMedGoogle Scholar
  142. 142.
    Urahama N, Ito M, Sada A, Yakushijin K, Yamamoto K, Okamura A, Minagawa K, Hato A, Chihara K, Roeder RG, Matsui T (2005) The role of transcriptional coactivator TRAP220 in myelomonocytic differentiation. Genes Cells 10:1127–1137PubMedGoogle Scholar
  143. 143.
    Ikezoe T, Bandobashi K, Yang Y, Takeuchi S, Sekiguchi N, Sakai S, Koeffler HP, Taguchi H (2006) HIV-1 protease inhibitor ritonavir potentiates the effect of 1, 25-dihydroxyvitamin D3 to induce growth arrest and differentiation of human myeloid leukemia cells via down-­regulation of CYP24. Leuk Res 30:1005–1011PubMedGoogle Scholar
  144. 144.
    Takahashi E, Nakagawa K, Suhara Y, Kittaka A, Nihei K, Konno K, Takayama H, Ozono K, Okano T (2006) Biological activities of 2alpha-substituted analogues of 1alpha, 25-dihydroxyvitamin D3 in transcriptional regulation and human promyelocytic leukemia (HL-60) cell proliferation and differentiation. Biol Pharm Bull 29:2246–2250PubMedGoogle Scholar
  145. 145.
    Suzuki T, Tazoe H, Taguchi K, Koyama Y, Ichikawa H, Hayakawa S, Munakata H, Isemura M (2006) DNA microarray analysis of changes in gene expression induced by 1, 25-dihydroxyvitamin D3 in human promyelocytic leukemia HL-60 cells. Biomed Res 27:99–109PubMedGoogle Scholar
  146. 146.
    Hughes PJ, Brown G (2006) 1Alpha, 25-dihydroxyvitamin D3-mediated stimulation of steroid sulphatase activity in myeloid leukaemic cell lines requires VDRnuc-mediated activation of the RAS/RAF/ERK-MAP kinase signalling pathway. J Cell Biochem 98:590–617PubMedGoogle Scholar
  147. 147.
    Hughes PJ, Lee JS, Reiner NE, Brown G (2008) The vitamin D receptor-mediated activation of phosphatidylinositol 3-kinase (PI3Kalpha) plays a role in the 1alpha, 25-dihydroxyvitamin D3-stimulated increase in steroid sulphatase activity in myeloid leukaemic cell lines. J Cell Biochem 103:1551–1572PubMedGoogle Scholar
  148. 148.
    Munker R, Kobayashi T, Elstner E, Norman AW, Uskokovic M, Zhang W, Andreeff M, Koeffler HP (1996) A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia. Blood 88:2201–2209PubMedGoogle Scholar
  149. 149.
    Muto A, Kizaki M, Yamato K, Kawai Y, Kamata-Matsushita M, Ueno H, Ohguchi M, Nishihara T, Koeffler HP, Ikeda Y (1999) 1, 25-Dihydroxyvitamin D3 induces differentiation of a retinoic acid-resistant acute promyelocytic leukemia cell line (UF-1) associated with expression of p21(WAF1/CIP1) and p27(KIP1). Blood 93:2225–2233PubMedGoogle Scholar
  150. 150.
    Shiohara M, Uskokovic M, Hisatake J, Hisatake Y, Koike K, Komiyama A, Koeffler HP (2001) 24-Oxo metabolites of vitamin D3 analogues: disassociation of their prominent antileukemic effects from their lack of calcium modulation. Cancer Res 61:3361–3368PubMedGoogle Scholar
  151. 151.
    ÓKelly J, Uskokovic M, Lemp N, Vadgama J, Koeffler HP (2006) Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the Akt/mTOR signaling pathway. J Steroid Biochem Mol Biol 100:107–16Google Scholar
  152. 152.
    Wang X, Studzinski GP (2001) Activation of extracellular signal-regulated kinases (ERKs) defines the first phase of 1, 25-dihydroxyvitamin D3-induced differentiation of HL60 cells. J Cell Biochem 80:471–482PubMedGoogle Scholar
  153. 153.
    Marcinkowska E (2001) Evidence that activation of MEK1, 2/Erk1, 2 signal transduction pathway is necessary for calcitriol-induced differentiation of HL-60 cells. Anticancer Res 21:499–504PubMedGoogle Scholar
  154. 154.
    Wang Q, Wang X, Studzinski GP (2003) Jun N-terminal kinase pathway enhances signaling of monocytic differentiation of human leukemia cells induced by 1, 25-dihydroxyvitamin D3. J Cell Biochem 89:1087–1101PubMedGoogle Scholar
  155. 155.
    Wang Q, Salman H, Danilenko M, Studzinski GP (2005) Cooperation between antioxidants and 1, 25-dihydroxyvitamin D3 in induction of leukemia HL60 cell differentiation through the JNK/AP-1/Egr-1 pathway. J Cell Physiol 204:964–974PubMedGoogle Scholar
  156. 156.
    Szabo E, Preis LH, Birrer MJ (1994) Constitutive cJun expression induces partial macrophage differentiation in U-937 cells. Cell Growth Differ 5:439–446PubMedGoogle Scholar
  157. 157.
    Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC (1995) SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett 364:229–233PubMedGoogle Scholar
  158. 158.
    Wang X, Rao J, Studzinski GP (2000) Inhibition of p38 MAP kinase activity up-regulates multiple MAP kinase pathways and potentiates 1, 25-dihydroxyvitamin D3-induced differentiation of human leukemia HL60 cells. Exp Cell Res 258:425–437PubMedGoogle Scholar
  159. 159.
    Ishii Y, Sakai S, Honma Y (2001) Pyridinyl imidazole inhibitor SB203580 activates p44/42 mitogen-activated protein kinase and induces the differentiation of human myeloid leukemia cells. Leuk Res 25:813–820PubMedGoogle Scholar
  160. 160.
    Weinberg RA (2006) The Biology of Cancer. Garland Science/Taylor & Francis/LLC, LondonGoogle Scholar
  161. 161.
    Hmama Z, Nandan D, Sly L, Knutson KL, Herrera-Velit P, Reiner NE (1999) 1alpha, 25-dihydroxyvitamin D3-induced myeloid cell differentiation is regulated by a vitamin D receptor-phosphatidylinositol 3-kinase signaling complex. J Exp Med 190:1583–1594PubMedGoogle Scholar
  162. 162.
    Marcinkowska E, Kutner A (2002) Side-chain modified vitamin D analogs require activation of both PI 3-K and erk1, 2 signal transduction pathways to induce differentiation of human promyelocytic leukemia cells. Acta Biochim Pol 49:393–406PubMedGoogle Scholar
  163. 163.
    Marcinkowska E, Wiedlocha A (2003) Phosphatidylinositol-3 kinase-dependent activation of Akt does not correlate with either high mitogenicity or cell migration induced by FGF-1. Anticancer Res 23:4071–4077PubMedGoogle Scholar
  164. 164.
    Gocek E, Kielbinski M, Marcinkowska E (2007) Activation of intracellular signaling pathways is necessary for an increase in VDR expression and its nuclear translocation. FEBS Lett 581:1751–1757PubMedGoogle Scholar
  165. 165.
    Berry DM, Antochi R, Bhatia M, Meckling-Gill KA (1996) 1, 25-Dihydroxyvitamin D3 stimulates expression and translocation of protein kinase Calpha and Cdelta via a nongenomic mechanism and rapidly induces phosphorylation of a 33-kDa protein in acute promyelocytic NB4 cells. J Biol Chem 271:16090–16096PubMedGoogle Scholar
  166. 166.
    Zanello SB, Collins ED, Marinissen MJ, Norman AW, Boland RL (1997) Vitamin D receptor expression in chicken muscle tissue and cultured myoblasts. Horm Metab Res 29:231–6PubMedGoogle Scholar
  167. 167.
    Marcinkowska E (2001) A run for a membrane vitamin D receptor. Biol Signals Recept 10:341–349PubMedGoogle Scholar
  168. 168.
    Okazaki T, Bielawska A, Bell RM, Hannun YA (1990) Role of ceramide as a lipid mediator of 1 alpha, 25-dihydroxyvitamin D3-induced HL-60 cell differentiation. J Biol Chem 265:15823–15831PubMedGoogle Scholar
  169. 169.
    Wang X, Studzinski GP (2004) Kinase suppressor of RAS (KSR) amplifies the differentiation signal provided by low concentrations 1, 25-dihydroxyvitamin D3. J Cell Physiol 198:333–342PubMedGoogle Scholar
  170. 170.
    Zhang Y, Yao B, Delikat S, Bayoumy S, Lin XH, Basu S, McGinley M, Chan-Hui PY, Lichenstein H, Kolesnick R (1997) Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 89:63–72PubMedGoogle Scholar
  171. 171.
    Wang X, Studzinski GP (2001) Phosphorylation of raf-1 by kinase suppressor of ras is inhibited by “MEK-specific” inhibitors PD 098059 and U0126 in differentiating HL60 cells. Exp Cell Res 268:294–300PubMedGoogle Scholar
  172. 172.
    Xing HR, Kolesnick R (2001) Kinase suppressor of Ras signals through Thr269 of c-Raf-1. J Biol Chem 276:9733–9741PubMedGoogle Scholar
  173. 173.
    Michaud NR, Therrien M, Cacace A, Edsall LC, Spiegel S, Rubin GM, Morrison DK (1997) KSR stimulates Raf-1 activity in a kinase-independent manner. Proc Natl Acad Sci USA 94:12792–12796PubMedGoogle Scholar
  174. 174.
    Morrison DK (2001) KSR: a MAPK scaffold of the Ras pathway? J Cell Sci 114:1609–1612PubMedGoogle Scholar
  175. 175.
    Wang X, Wang TT, White JH, Studzinski GP (2006) Induction of kinase suppressor of RAS-1(KSR-1) gene by 1, alpha25-dihydroxyvitamin D3 in human leukemia HL60 cells through a vitamin D response element in the 5′′-flanking region. Oncogene 25:7078–7085PubMedGoogle Scholar
  176. 176.
    Garay E, Donnelly R, Wang X, Studzinski GP (2007) Resistance to 1, 25D-induced differentiation in human acute myeloid leukemia HL60–40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor. J Cell Physiol 213:816–825PubMedGoogle Scholar
  177. 177.
    Gocek E, Kielbinski M, Wylob P, Kutner A, Marcinkowska E (2008) Side-chain modified vitamin D analogs induce rapid accumulation of VDR in the cell nuclei proportionately to their differentiation-inducing potential. Steroids 73:1359–1366PubMedGoogle Scholar
  178. 178.
    Wang X, Studzinski GP (2006) Raf-1 signaling is required for the later stages of 1, 25-dihydroxyvitamin D3-induced differentiation of HL60 cells but is not mediated by the MEK/ERK module. J Cell Physiol 209:253–260PubMedGoogle Scholar
  179. 179.
    Jamshidi F, Zhang J, Harrison JS, Wang X, Studzinski GP (2008) Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1, 25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling. Cell Cycle 7:917–924PubMedGoogle Scholar
  180. 180.
    Porras A, Muszynski K, Rapp UR, Santos E (1994) Dissociation between activation of Raf-1 kinase and the 42-kDa mitogen-activated protein kinase/90-kDa S6 kinase (MAPK/RSK) cascade in the insulin/Ras pathway of adipocytic differentiation of 3T3L1 cells. J Biol Chem 269:12741–12748PubMedGoogle Scholar
  181. 181.
    Kuo WL, Abe M, Rhee J, Eves EM, McCarthy SA, Yan M, Templeton DJ, McMahon M, Rosner MR (1996) Raf, but not MEK or ERK, is sufficient for differentiation of hippocampal neuronal cells. Mol Cell Biol 16:1458–1470PubMedGoogle Scholar
  182. 182.
    Dhillon AS, Pollock C, Steen H, Shaw PE, Mischak H, Kolch W (2002) Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259. Mol Cell Biol 22:3237–3246PubMedGoogle Scholar
  183. 183.
    Godyn JJ, Xu H, Zhang F, Kolla S, Studzinski GP (1994) A dual block to cell cycle progression in HL60 cells exposed to analogues of vitamin D3. Cell Prolif 27:37–46PubMedGoogle Scholar
  184. 184.
    Cicero S, Herrup K (2005) Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J Neurosci 25:9658–9668PubMedGoogle Scholar
  185. 185.
    Chen F, Studzinski GP (1999) Cyclin-dependent kinase 5 activity enhances monocytic phenotype and cell cycle traverse in 1, 25-dihydroxyvitamin D3-treated HL60 cells. Exp Cell Res 249:422–428PubMedGoogle Scholar
  186. 186.
    Chen F, Rao J, Studzinski GP (2000) Specific association of increased cyclin-dependent kinase 5 expression with monocytic lineage of differentiation of human leukemia HL60 cells. J Leukoc Biol 67:559–566PubMedGoogle Scholar
  187. 187.
    Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371:419–423PubMedGoogle Scholar
  188. 188.
    Chen F, Studzinski GP (2001) Expression of the neuronal cyclin-dependent kinase 5 activator p35Nck5a in human monocytic cells is associated with differentiation. Blood 97:3763–3767PubMedGoogle Scholar
  189. 189.
    Chen F, Wang Q, Wang X, Studzinski GP (2004) Up-regulation of Egr1 by 1, 25-dihydroxyvitamin D3 contributes to increased expression of p35 activator of cyclin-dependent kinase 5 and consequent onset of the terminal phase of HL60 cell differentiation. Cancer Res 64:5425–5433PubMedGoogle Scholar
  190. 190.
    Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci US A 92:7686–7689Google Scholar
  191. 191.
    Foster JS, Fernando RI, Ishida N, Nakayama KI, Wimalasena J (2003) Estrogens down-regulate p27Kip1 in breast cancer cells through Skp2 and through nuclear export mediated by the ERK pathway. J Biol Chem 278:41355–41366PubMedGoogle Scholar
  192. 192.
    Park BH, Qiang L, Farmer SR (2004) Phosphorylation of C/EBPbeta at a consensus extracellular signal-regulated kinase/glycogen synthase kinase 3 site is required for the induction of adiponectin gene expression during the differentiation of mouse fibroblasts into adipocytes. Mol Cell Biol 24:8671–8680PubMedGoogle Scholar
  193. 193.
    Buck M, Poli V, Hunter T, Chojkier M (2001) C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Mol Cell 8:807–816PubMedGoogle Scholar
  194. 194.
    Pan Z, Hetherington CJ, Zhang DE (1999) CCAAT/enhancer-binding protein activates the CD14 promoter and mediates transforming growth factor beta signaling in monocyte development. J Biol Chem 274:23242–23248PubMedGoogle Scholar
  195. 195.
    Ji Y, Studzinski GP (2004) Retinoblastoma protein and CCAAT/enhancer-binding protein beta are required for 1, 25-dihydroxyvitamin D3-induced monocytic differentiation of HL60 cells. Cancer Res 64:370–377PubMedGoogle Scholar
  196. 196.
    Studzinski GP, Wang X, Ji Y, Wang Q, Zhang Y, Kutner A, Harrison JS (2005) The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway. J Steroid Biochem Mol Biol 97:47–55PubMedGoogle Scholar
  197. 197.
    Penna G, Adorini L (2000) 1 Alpha, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164:2405–2411PubMedGoogle Scholar
  198. 198.
    Zhu K, Glaser R, Mrowietz U (2002) Vitamin D3 and analogues modulate the expression of CSF-1 and its receptor in human dendritic cells. Biochem Biophys Res Commun 297:1211–1217PubMedGoogle Scholar
  199. 199.
    Garzon R, Pichiorri F, Palumbo T, Visentini M, Aqeilan R, Cimmino A, Wang H, Sun H, Volinia S, Alder H, Calin GA, Liu CG, Andreeff M, Croce CM (2007) MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene 26:4148–4157PubMedGoogle Scholar
  200. 200.
    Sharma P, Veeranna SM, Amin ND, Sihag RK, Grant P, Ahn N, Kulkarni AB, Pant HC (2002) Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. J Biol Chem 277:528–534PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUMDNJ-New Jersey Medical SchoolNewarkUSA

Personalised recommendations