Cholecalciferol (vitamin D3) inhibits growth and invasion by up-regulating nuclear receptors and 25-hydroxylase (CYP27A1) in human prostate cancer cells
Epidemiological evidence suggests an inverse relationship
between prostate cancer and serum vitamin D levels. We examined the ability of
cholecalciferol (vitamin D(3)), 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-alpha (RXR-alpha),
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)D(3) and of 25(OH)D(3) 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. Tokar EJ, Webber MM. Clin Exp Metastasis. 2005;22(3):275-84.
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