Page 27 - Vitamin D and Cancer

14 H.S. Cross

PCNA (proliferating cell nuclear antigen) and for cyclin D1, while that for p21,
a cyclin-dependent kinase inhibitor, was diminished. Mice on a calcium-deficient
diet also expressed CYP24A1 mRNA at a six- to eightfold higher level than their
counterparts on a 0.9% calcium diet [27]. Interestingly, CYP27B1 mRNA was
significantly up-regulated in animals on 0.04% compared to 0.9% calcium as
well, though in female mice only [129]. Importantly, measurement of 1,25-(OH)
D concentrations in mucosal homogenates by a newly developed assay [127]
3
indicated that up-regulation of CYP27B1 by low calcium is translated into
increased CYP27B1 protein activity causing accumulation of 1,25-(OH)D in
3
colonic mucosal cells. In parallel, in these cells apoptotic pathways, i.e., expres-
sion of the downstream effector proteases, caspase-3 and of caspase 7, are stimu-
lated. This strongly suggests that enhanced synthesis of 1,25-(OH)D in females
3
overrides the gender-independent stimulatory effect of low calcium on CYP24A1-
mediated vitamin D catabolism, thereby providing protection against incipient
hyperproliferation induced by inadequate calcium nutrition. This enhanced syn-
thesizing activity occurred in the proximal colon only and suggests that there may
be site-specific action of 17b-estradiol. As mentioned previously, the estrogen
receptor ESR1 is more methylated (inactivated) in the human distal than in the
proximal colon [72] (see also Sect. 1.2.3).
At present it is not clear whether signals from low luminal calcium are trans-
duced by the calcium sensing receptor (CaR). Alternatively, a lack of calcium is
known to increase concentrations of free bile acids in the gut lumen. Of these, litho-
cholic acid by binding to the VDR can induce expression of CYP24A1 [101]. Our
results suggest that in humans also calcium supplementation could lower the risk of
colorectal cancer because high dietary calcium suppresses vitamin D catabolism
and this would favor accumulation of 1,25-(OH)D in the colon mucosa.
3
Furthermore, 1,25-(OH)D would increase expression of the CaR by binding to a
3
vitamin D responsive element in its promoter region [102].

1.3.2 Regulation of the Vitamin D System by Phytoestrogens

It can be inferred that in human colonocytes, estrogenic compounds have positive
effects on endogenous synthesis of 1,25-(OH) D and consequently on VDR-
2 3
mediated anti-inflammatory and antimitogenic actions (see Sect. 1.2.3). In this
context, it is of interest that in East Asian populations the risk of cancers of sex
hormone-responsive organs, viz., breast and prostate gland, as well as of the col-
orectum is clearly lower than elsewhere. This has been traced to the typical diet in
this part of the world, which is rich in soy products and therefore contains high
amounts of phytoestrogens. Of these, genistein induced CYP27B1 and reduced
CYP24A1 expression and activity in a mouse model and in human colon adenocar-
cinoma-derived cell lines [103], while daidzein, another phytoestrogen prominent
in soy and, importantly, its metabolite equol, which is strongly active in other bio-
logical systems, did not affect any of the colonic vitamin D hydroxylases [70].