Page 50 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 37

contain more ROS, which in turn can damage DNA and prevent proper function of
DNA repair machinery. Also the induction of cytokines and growth factors associ-
ated with inflammation act to increase the proliferative potential of the cells.
NF-kB is a key mediator of inflammation and the VDR attenuates this process by
negatively regulating NF-kB signaling [153]. This control by VDR is underscored
by studies showing Vdr-/- mice are more sensitive to chemicals that induce inflam-
mation than their wild-type counterparts [154]. The normally protective effect of
inflammation that occurs under other conditions is lost through VDR-mediated
suppression but is compensated for by the induction of a cohort of antimicrobial
and antifungal genes [155–157]. The induction of antimicrobials not only prevents
infection in damaged tissue but can be cytotoxic for cells with increased levels of
anion phospholipids within their membranes, a common feature of transformed
cells [158]. Finally, and most recently, network strategies have been used in differ-
ent strains of mice with altered sensitivity toward skin cancer. Remarkably, in such
unbiased screens, the VDR emerges as a key nodal control point in determining
sensitivity toward skin tumors as it regulates both turnover of self-renewal and
inflammatory infiltrate [159].
The key question, and central to exploiting any therapeutic potential of this
receptor, is why should the VDR exert such pleiotropic actions? One possible
explanation for this pleiotropism is that it represents an adaptation of the skin to UV
exposure, coupling the paramount importance of initiating 1a,25(OH) D synthesis
2 3
with protection of cell and tissue integrity. Thus, VDR actions are able to maximize
UV-initiated synthesis of 1a,25(OH) D production, whilst controlling the extent of
2 3
local inflammation that can result from sun exposure. To compensate for the poten-
tial loss of protection associated with immunosuppression, the VDR mediates a
range of antimicrobial actions. Equally, local genomic protection is ensured through
the upregulation of target genes which induce G /G arrest, cooperation with p53,
0 1
and the induction of cell differentiation. It remains a tantalizing possibility that the
functional convergence between p53 family and VDR signaling, which arose in the
dermis as an evolutionary adaptation to counterbalance the conflicting physiologi-
cal requirements of vitamin D synthesis and genome protection, are sustained in
epithelial systems, such as the lining of the mammary gland, to protect against
genotoxic insults derived from either the environment or local inflammation.

2.3.3 Programmed Cell Death

VDR actions, notably in MCF-7 breast cancer cells, are associated with a profound
and rapid induction of apoptosis, irrespective of p53 content. This may reflect the
VDR role in the involution of the post-lactating mammary gland. The direct tran-
scriptional targets which regulate these actions remain elusive, although there is
evidence of an involvement of the BAX family of proteins [160, 161]. Induction of
programmed cell death following 1a,25(OH) D treatment is also associated with
3
2
increased ROS generation. 1a,25(OH) D treatment up-regulates VDUP1 encoding
2 3