Page 237 - Vitamin D and Cancer

224 C.M. Barnett and T.M. Beer

When VDR is activated it binds to the promoter regions of specific genes and
regulates the transcription of mRNA of these genes. The VDR (once activated
by vitamin D) forms a heterodimer with the retinoid-X receptor (RXR) and
then binds to the regulatory region of the gene in the presence of a coactivator
and corepressor complex. Many genes involving calcium and bone metabolism
including osteoclastin [24] and osteopontin [25] are regulated this way. In addi-
tion, other genes regulating the cell cycle, apoptosis, and cell proliferation have
been found to have a vitamin D response element (VDRE) and are induced or
down-regulated by vitamin D. Some genes with vitamin D response elements
that are activated by vitamin D include p21 [26] and GADD45 [27], which play
an important role in cell cycle regulation, and CYP2A1, [11, 28] which encodes
24-hydroxylase. Notable genes down-regulated by vitamin D include PTH [29]
and CYP2B1 [8], which regulate 1-alpha-hydroxylase production. Also, vita-
min D has been shown to down-regulate insulin-like growth factor [30] and
Bcl-2 [31]. Through the regulation of these genes as well many others, vitamin
D can shift the balance of cell survival signals in favor of apoptosis and growth
arrest. There are many other vitamin D-regulated genes and a partial list of
these is provided in Table 10.1. Notably, many of these genes are important
regulators of cell growth and apoptosis.
In addition to VDR-mediated activities of vitamin D, there are rapid non-
genomic signals induced by vitamin D. Examples include rapid intestinal absorption
of calcium induced by vitamin D [32] as well as the induction of signaling cascades
such as Raf-MEK-MAPK-ERK signaling pathway [11, 33–35] and protein kinase
C [36] among others. These rapid signals may be mediated by translocation of the
VDR to the plasma membrane [11, 37] (Table 10.2).
Because the VDR regulates so many genes including those effecting cell growth
and cancer development, many recent studies have been devoted to looking at dif-
ferent genetic variants of the VDR and their relation to prostate cancer risk. Most
of these studies have been focused on five VDR gene polymorphisms, the poly-A
microsatellite, and four restriction sites: FokI, BsmI, ApaI, and TaqI. Much like
epidemiologic studies with serum levels of vitamin D, some studies involving these
polymorphisms have shown strong associations with increased prostate cancer risk,
but overall results between different studies are inconclusive [13, 38–42].

10.4 Mechanisms of Anti-neoplastic Activity

Because there are so many different genes affected by vitamin D, different
anti-neoplastic activity mechanisms predominate under different experimental con-
ditions, and in different tumor models. Nevertheless, vitamin D activity against
prostate cancer is seen across a range of tumor models.
Not surprisingly, given that multiple cell cycle regulatory genes are regulated by
vitamin D, a number of investigators have demonstrated vitamin D-induced growth
arrest in G1 [11, 26, 43–46]. This has been attributed, at least in part, to transcriptional