Page 55 - Vitamin D and Cancer

42 J. Thorne and M.J. Campbell

Phylogenetic classification has defined seven NR subfamilies, and within these
the VDR is in the group 1 subfamily, sharing homology with the LXRs and FXR,
and more distantly the PPARs [203, 204]. The receptors within this subfamily pref-
erentially form homo- or heterodimeric complexes with RXR acting as a common
central partner for VDR, PPARs, LXRs, and FXR. Thus, the receptors in the group
appear to be all responsive to either bile acid or xenobiotic receptors and, therefore,
widely integrated with bile acid homeostasis and detoxification. In keeping with
this capacity, the bile acid lithocholic acid (LCA) has recently been shown to be a
potent ligand for the VDR all be it with lower millimolar affinity [193].
VDR biology participates in at least three fundamental areas of biology required
for human health, and which are disrupted in human disease. It participates in the
regulation of serum calcium, and by implication the maintenance of bone integrity;
the control of cell proliferation and differentiation; and by implication the disrup-
tion of these actions in malignancy; and as a modifier of immune responses and by
implication contributes toward auto-immune diseases [205]. The divergence of
these actions may make the VDR a particularly challenging receptor to understand
in terms of biology and to exploit therapeutically.
Specifically dietary-derived fatty acids and bile acids cycle rapidly in response
to dietary intake and work hormonally to coordinate multiple aspects of tissue func-
tion in response to changing energetic status. Thus, it is unlikely that the VDR
alone plays a key and dominant role in cell and tissue function by acting singularly,
but instead is intimately linked to the actions of related NRs (e.g., PPARs, FXR,
and LXR) and cofactors. In this manner, the actions of the VDR to regulate cell
growth and differentiation, as part of a network of environmental and dietary sens-
ing receptors, may be the central and common function for the VDR. The differen-
tiated phenotype of these cells then participates in diverse biology that range from
calcium transport to dermis formation and mammary gland function.
For “next generation” developments to occur it will be necessary to adopt a
broader view of VDR signaling. Historically, researchers have studied the abilities
of single NRs such as the VDR to regulate a discrete group of gene targets and
influence cell function. This has led to substantial knowledge concerning many of
these receptors, individually. Cell and organism function, however, depends on the
dynamic interactions of a collection of receptors, through the networks that link
them, and against the backdrop of intrinsic cellular programs, such as those govern-
ing development and differentiation.
In such a view, it is apparent that NRs act as an adaptive homeostatic network in
several tissues to sense environmental dietary and xenobiotic lipophilic compounds
and sustain the cell, for example, through the diurnal patterns of fast and feeding
(reviewed in [204, 206]). The VDR was originally described for a central endocrine
role in maintenance of serum calcium levels. Similarly, the FXR and LXRs were
described for their central role in cholesterol metabolism and bile acid synthesis in
the enterohepatic system. However, their expression in multiple target tissues such
a broader role. Examination of the known target genes for VDR, RARs, PPARs,
FXR, and LXRs reveals that they share in common the regulation of cell cycle,
programmed cell death, differentiation, and xenobiotic and metabolic clearance.