Clinical & Experimental Metastasis

, Volume 22, Issue 3, pp 275–284

Cholecalciferol (Vitamin D3) Inhibits Growth and Invasion by Up-regulating Nuclear Receptors and 25-Hydroxylase (CYP27A1) in Human Prostate Cancer Cells

Article

DOI: 10.1007/s10585-005-8393-z

Cite this article as:
Tokar, E.J. & Webber, M.M. Clin Exp Metastasis (2005) 22: 275. doi:10.1007/s10585-005-8393-z

Abstract

Epidemiological evidence suggests an inverse relationship between prostate cancer and serum vitamin D levels. We examined the ability of cholecalciferol (vitamin D3), a calcitriol precursor, to inhibit or reverse cellular changes associated with malignant transformation and invasion and explored its mechanisms of action. The RWPE2-W99 human prostate epithelial cell line, which forms slow-growing tumors in nude mice, was used because it mimics the behavior of the majority of primary human prostate cancers. Cholecalciferol, at physiological levels: (i) inhibited anchorage-dependent and -independent growth; (ii) induced differentiation by decreasing vimentin expression with a concomitant decrease in motility/chemotaxis; (iii) decreased MMP-9 and MMP-2 activity with concomitant decrease in invasion; and (iv) exerted its effects by up-regulating vitamin D receptor (VDR), retinoid-X receptor-α (RXR-α), and androgen receptor (AR) in a dose-dependent manner. Furthermore, we found that RWPE2-W99 prostate cancer cells, similar to RWPE-1 cells (Tokar and Webber. Clin Exp Metast 2005; 22: 265–73), constitutively express the enzyme 25-hydroxylase CYP27A1 which is markedly up-regulated by cholecalciferol. Cholecalciferol has effects similar to those of calcitriol on growth, MMP activity, and VDR. The ability of CYP27A1 to catalyze the conversion of cholecalciferol to 25(OH)D3 and of 25(OH)D3 to calcitriol has been reported. RWPE2-W99 cells, similar to RWPE-1 cells, appear to have the rare ability to locally convert cholecalciferol to the active hormone calcitriol. Because it can inhibit cellular changes associated with malignant transformation and invasion, we propose that cholecalciferol may be an effective agent for the treatment of prostate cancer.

Keywords

cholecalciferol CYP27A1 25-hydroxylase invasion MMPs prostate cancer vitamin D 

Abbreviations

25(OH)D3

25-hydroxyvitamin D3

AR

androgen receptor

CFE

colony forming efficiency

MMP

matrix metalloproteinase

MTT

3-[4,5-dimethylthiazol-2-yl]-2,5-diphenly tetarzolium

PAI-1

plasminogen activator inhibitor

PSA

prostate specific antigen

PZ

peripheral zone

RXR

retinoid X receptor

UPA

urokinase-type plasminogen activator

UVR

ultraviolet radiation

VDR

vitamin D receptor

Copyright information

© Springer 2005

Authors and Affiliations

  1. 1.Departments of Zoology and MedicineMichigan State UniversityEast LansingUSA
  2. 2.Michigan State UniversityEast LansingUSA

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