Page 236 - Vitamin D and Cancer

10 Vitamin D and Prostate Cancer 223

This endocrine enzyme is located predominately in the kidney, but has also been
found in other tissues such as the colon and the prostate [3–7]. The circulating
levels of 1,25-OH vitamin D are tightly regulated by calcium levels and parathy-
2
roid hormone. Renal 1-alpha-hydroxylase activity is enhanced by hypocalcemia
through transcriptional regulation. The expression of the CYP27B1 gene, which
encodes 1-alpha-hydroxylase, is upregulated by parathyroid hormone [8]. 1,25-
OH vitamin D in turn inhibits transcription of 1-alpha-hydroxylase creating a
2
regulatory feedback loop [9, 10]. In contrast, non-renal 1-alpha-hydroxylase, that
is responsible for autocrine and paracrine, but not endocrine vitamin D activation,
is thought to be constitutively active [7, 11]. Unlike its renal counterpart, extra-
renal 1-alpha-hydroxylase is not down-regulated by its downstream product, 1,25-
OH vitamin D [12]. Thus, tissues that express 1-alpha-hydroxylase, including
2
potentially certain tumors, may experience tissue 1,25-OH vitamin D levels that
2
reflect circulating levels of the substrate (25-OH vitamin D). 1,25-OH vitamin D
2
also induces the CYP27A1 gene that encodes 24-hydroxylase. This enzyme
catalyses 24-hydroxylation of 25-OH vitamin D, creating, 24,25-OH vitamin D, a
2
hormonally inactive alternative to 1,25-OH vitamin D [9, 11, 13]. Local activity
2
of the competing 24-hydroxylase in some cancer tissues, may also impact on tissue
1,25-OH vitamin D concentrations by diverting the substrate [11, 14].
2
Prostate carcinoma cell lines express vitamin D receptors (VDR) [15–17]. VDR
expression in human prostate cancer specimens has also been reported [18].
Interestingly, prostate cell lines also express 1-alpha-hydroxylase [3, 5]. However,
it has been shown in cell culture that prostate cancer cells have reduced
1- alpha-hydroxylase activity when compared to normal prostate epithelial cells,
[3, 19]. As a consequence, prostate cancer cells may lose the ability to convert
25-OH vitamin D to 1,25-OH vitamin D. Loss of the ability to locally produce
2
activated vitamin D may result in the loss of an important break on cancer cell
proliferation. This hypothesis has led to the suggestion that 1-alpha-hydroxylase
may act as a tumor suppressor gene [20]. Because VDR exerts predominantly
growth inhibitory effects on prostate cancer cell lines, it is plausible that loss of the
autocrine vitamin D loop with reduced 1-alpha-hydroxylase activity contributes to
the progression of prostate cancer [21]. Also, VDR activity has been shown to be
altered in prostate cancer cells, with decreased ligand-inducible DNA binding
activity, altered recruitment of coregulators SRC-1 and CBP, and increased recruit-
ment of SMRT corepressor [22]. These alterations may further exacerbate the
effects of a relative deficiency of 1,25-OH vitamin D concentrations in prostate
2
cancer.

10.3 The Biologic Activity of Vitamin D in Prostate Cancer

Vitamin D activity involves both rapid induction of cell signaling pathways,
and genomic receptor-mediated pathways. The vitamin D receptor is an intrac-
ellular steroid receptor that acts as a ligand activated transcription factor [23].