Skip to main content

Advertisement

SpringerLink
Log in

Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Vitamin D and its analogs are potent inhibitors of colorectal cancer growth and metastasis. A number of recent studies have defined the intersections between the β-catenin-TCF pathway (a known contributor to colorectal cancer progression) and the vitamin D receptor (VDR) pathway, shedding light on the underlying mechanisms. Vitamin D also regulates the innate immune response, and as such influences susceptibility to inflammatory bowel disease, a predisposing factor in colorectal cancer. Understanding the role of vitamin D in these different contexts will enable development of next generation vitamin D analogs that will serve as both chemopreventatives and cancer therapeutics, without the accompanying side effects of hypercalcemia usually associated with high vitamin D intake. This review summarizes the mechanisms of action of vitamin D and the VDR in the context of the gastrointestinal tract and colorectal carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Beildeck ME, Gelmann EP, Byers SW. Cross-regulation of signaling pathways: an example of nuclear hormone receptors and the canonical Wnt pathway. Exp Cell Res. 2010;16:1763–72.

    Article  Google Scholar 

  2. Thorne J, Campbell MJ. The vitamin D receptor in cancer. Proc Nutr Soc. 2008;67:115–27.

    Article  PubMed  CAS  Google Scholar 

  3. Shah S, Hecht A, Pestell R, Byers SW. Trans-repression of beta-catenin activity by nuclear receptors. J Biol Chem. 2003;278:48137–45.

    Article  PubMed  CAS  Google Scholar 

  4. Shah S, Islam MN, Dakshanamurthy S, Rizvi I, Rao M, Herrell R, et al. The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell. 2006;21:799–809.

    Article  PubMed  Google Scholar 

  5. Touvier M, Chan DS, Lau R, Aune D, Vieira R, Greenwood DC, et al. Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and colorectal cancer risk. Canc Epidemiol Biomarkers Prev. 2011;20:1003–16.

    Article  CAS  Google Scholar 

  6. Campbell FC, Xu H, El-Tanani M, Crowe P, Bingham V. The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control. Biochem Pharmacol. 2010;79:1–9.

    Article  PubMed  CAS  Google Scholar 

  7. Beildeck MR, Byers SW. Vitamin D analogues in colon cancer prevention and care. Curr Colorectal Cancer Rep. 2009;5:185–96.

    Article  Google Scholar 

  8. Pálmer HG, Sánchez-Carbayo M, Ordóñez-Morán P, Larriba MJ, Cordón-Cardó C, Muñoz A. Genetic signatures of differentiation induced by 1alpha,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res. 2003;63:7799–806.

    PubMed  Google Scholar 

  9. Wang TT, Tavera-Mendoza LE, Laperriere D, Libby E, MacLeod NB, Nagai Y, et al. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005;19:2685–95.

    Article  PubMed  CAS  Google Scholar 

  10. Mullin GE, Dobs A. Vitamin d and its role in cancer and immunity: a prescription for sunlight. Nutr Clin Pract. 2007;22:305–22.

    Article  PubMed  Google Scholar 

  11. Belleli A, Shany S, Levy J, Guberman R, Lamprecht SA. A protective role of 1,25-dihydroxyvitamin D3 in chemically induced rat colon carcinogenesis. Carcinogenesis. 1992;13:2293–8.

    Article  PubMed  CAS  Google Scholar 

  12. Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K, et al. Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage. Carcinogenesis. 2001;22:1429–35.

    Article  PubMed  CAS  Google Scholar 

  13. Zheng W, Wong KE, Zhang Z, Dougherty U, Mustafi R, Kong J, Deb DK, Zheng H, Bissonnette M, Li YC. Inactivation of the vitamin D receptor in APC(min/+) mice reveals a critical role for the vitamin D receptor in intestinal tumor growth. Int J Cancer. 2011;Epub Feb 15.

  14. Rochel N, Wurtz JM, Mitschler A, et al. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 2000;5:173–9.

    Article  PubMed  CAS  Google Scholar 

  15. Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci USA. 1995;92:3046–50.

    Article  PubMed  CAS  Google Scholar 

  16. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3 beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272:1023–6.

    Article  PubMed  CAS  Google Scholar 

  17. Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW. Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. J Biol Chem. 1997;272:24735–8.

    Article  PubMed  CAS  Google Scholar 

  18. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, et al. Functional interaction of b-catenin with the transcription factor LEF-1. Nature. 1996;382:638–42.

    Article  PubMed  CAS  Google Scholar 

  19. Cong F, Schweizer L, Chamorro M, Varmus H. Requirement for a nuclear function of beta-catenin in Wnt signaling. Mol Cell Biol. 2003;23:8462–70.

    Article  PubMed  CAS  Google Scholar 

  20. Barth AI, Näthke IS, Nelson WJ. Cadherins, catenins and APC protein: interplay between cytoskeletal complexes and signaling pathways. Curr Opin Cell Biol. 1997;9:683–90.

    Article  PubMed  CAS  Google Scholar 

  21. Gavert N, Ben-Zéev A. beta-Catenin signaling in biological control and cancer. J Cell Biochem. 2007;102:820–8.

    Article  PubMed  CAS  Google Scholar 

  22. Kinzler KW, Nilbert MC, Vogelstein B, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991;251:1366–70.

    Article  PubMed  CAS  Google Scholar 

  23. Easwaran V, Pishvaian M, Salimuddin S, Byers S. Cross-regulation of beta-catenin-LEF/TCF and retinoid signaling pathways. Curr Biol. 1999;9:1415–8.

    Article  PubMed  CAS  Google Scholar 

  24. Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, et al. 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. 2001;154:369–87.

    Article  PubMed  CAS  Google Scholar 

  25. Malloy PJ, Xu R, Peng L, Clark PA, Feldman D. A novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Mol Endocrinol. 2002;16:2538–46.

    Article  PubMed  CAS  Google Scholar 

  26. Sivanesan D, Rajnarayanan RV, Doherty J, Pattabiraman N. In-silico screening using flexible ligand binding pockets: a molecular dynamics-based approach. J Comput Aided Mol Des. 2005;19:213–28.

    Article  PubMed  CAS  Google Scholar 

  27. Eelen G, Verlinden L, Bouillon R, De Clercq P, Muñoz A, Verstuyf A. CD-ring modified vitamin D3 analogs and their superagonistic action. J Steroid Biochem Mol Biol. 2010;121:417–9.

    Article  PubMed  CAS  Google Scholar 

  28. Egan JB, Thompson PA, Vitanov MV, Bartik L, Jacobs ET, Haussler MR, et al. Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulates beta-catenin activity in colon cancer cells. Mol Carcino. 2010;49:337–52.

    CAS  Google Scholar 

  29. Palmer HG, Larriba MJ, Garcia JM, Ordonez-Moran P, Pena C, Peiro S, et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat Med. 2004;10:917–9.

    Article  PubMed  CAS  Google Scholar 

  30. Peña C, García JM, Silva J, García V, Rodríguez R, Alonso I, et al. E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Hum Mol Genet. 2005;14:3361–70.

    Article  PubMed  Google Scholar 

  31. Larriba MJ, Bonilla F, Muñoz A. The transcription factors Snail1 and Snail2 repress vitamin D receptor during colon cancer progression. J Steroid Biochem Mol Biol. 2010;121:106–9.

    Article  PubMed  CAS  Google Scholar 

  32. Larriba MJ, Martín-Villar E, García JM, Pereira F, Peña C, de Herreros AG, et al. Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis. 2009;30:1459–68.

    Article  PubMed  CAS  Google Scholar 

  33. Aguilera O, Pena C, Garcia JM, Larriba MJ, Ordonez-Moran P, Navarro D, et al. The Wnt antagonist DICKKOPF-1 gene is induced by 1 alpha,25-dihydroxyvitamin D-3 associated to the differentiation of human colon cancer cells. Carcinogenesis. 2007;28:1877–84.

    Article  PubMed  CAS  Google Scholar 

  34. Pendas-Franco N, Aguilera O, Pereira F, Gonzalez-Sancho JM, Munoz A. Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Res. 2008;28:2613–23.

    PubMed  CAS  Google Scholar 

  35. Norman AW. Vitamin D receptor: new assignments for an already busy receptor. Endocrinology. 2006;147:5542–8.

    Article  PubMed  CAS  Google Scholar 

  36. Mizwicki MT, Bula CM, Bishop JE, Norman AW. A perspective on how the Vitamin D sterol/Vitamin D receptor (VDR) conformational ensemble model can potentially be used to understand the structure-function results of A-ring modified Vitamin D sterols. J Steroid Biochem Mol Biol. 2005;97:69–82.

    Article  PubMed  CAS  Google Scholar 

  37. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–96.

    Article  PubMed  CAS  Google Scholar 

  38. Cippitelli M, Santoni A. Vitamin D3: a transcriptional modulator of the interferon-gamma gene. Eur J Immunol. 1998;28:3017–30.

    Article  PubMed  CAS  Google Scholar 

  39. Boonstra A. 1 Alpha,25-dihydroxyvitamin D3 has a direct effecton naive CD4(_) T cells to enhance the development of Th2 cells. J Immunol. 2001;167:4974–80.

    PubMed  CAS  Google Scholar 

  40. Froicu M, Cantorna MT. Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol. 2007;8:5.

    Article  PubMed  Google Scholar 

  41. Liu PT, Krutzik SR, Modlin RL. Therapeutic implications of the TLR and VDR partnership. Trends Mol Med. 2007;13:117–24.

    Article  PubMed  Google Scholar 

  42. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–3.

    Article  PubMed  CAS  Google Scholar 

  43. Gómez García EB, Knoers NV. Gardner’s syndrome (familial adenomatous polyposis): a cilia-related disorder. Lancet Oncol. 2009;10:727–35.

    Article  PubMed  Google Scholar 

  44. Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Gastroenterol. 2006;101:385–98.

    Article  PubMed  Google Scholar 

  45. Lipkin M. New rodent models for studies of chemopreventive agents, J Cell Biochem. 1997;Suppl. 28–29:144–7.

    Article  Google Scholar 

  46. Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA. 1997;94:9831–5.

    Article  PubMed  CAS  Google Scholar 

  47. Teichert A, Elalieh H, Bikle D. Disruption of the hedgehog signaling pathway contributes to the hair follicle cycling deficiency in Vdr knockout mice. J Cell Physiol. 2010;225:482–9.

    Article  PubMed  CAS  Google Scholar 

  48. Palmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis. PLoS ONE. 2008;3:e1483.

    Article  PubMed  Google Scholar 

  49. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011;140:1807–16.

    Article  PubMed  CAS  Google Scholar 

Download references

Financial support

The author’s studies were funded by NIH R01CA129813, NIH R01 DK58196, NIH 1 P01 CA130821 (SWB) NIH R21CA156188 (YSB).

Author information

Authors and Affiliations

  1. Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, E415 Research Building, 3970 Reservoir Road, NW, Washington, DC, 20057, USA

    Stephen W. Byers, Tracey Rowlands, Marcy Beildeck & Yong-Sik Bong

Authors
  1. Stephen W. Byers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tracey Rowlands
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcy Beildeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong-Sik Bong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen W. Byers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Byers, S.W., Rowlands, T., Beildeck, M. et al. Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment. Rev Endocr Metab Disord 13, 31–38 (2012). https://doi.org/10.1007/s11154-011-9196-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-011-9196-y

Keywords

Search

Navigation