Page 51 - Vitamin D and Cancer

38 J. Thorne and M.J. Campbell

vitamin D up-regulated protein 1, which binds to the disulfide reducing protein
thioredoxin and inhibits its ability to neutralize ROS, thereby potentiating stress-
induced apoptosis [162, 163]. In other cells, the apoptotic response is delayed and
not so pronounced, and probably reflecting less direct effects. Taken together, these
data suggest that extent and timing of apoptotic events depend on the integration of
VDR actions with other cell signaling systems. This regulation of apoptosis in
human cancer cell lines reflects, of course, the absence of apoptosis in chondro-
cytes in the Vdr -/- animals [7].

2.4 Mechanisms of Resistance Toward the VDR

A major limitation in the therapeutic exploitation of VDR in cancer therapies is the
resistance of cancer cells toward 1a,25(OH) D . An understanding of the molecular
3
2
mechanisms of resistance has emerged.

2.4.1 Reduced Local Availability of 1a,25(OH) D
2 3

Tumors, such as breast cancer appear to distort the VDR signaling axis locally,
with reduced CYP27b1 mRNA and protein levels, and comparative genome
hybridization studies have found that CYP24 is amplified in human breast cancer
[164, 165]. Thus, cancer cells maybe associated with low circulating concentrations
of 25(OH)D , arising as a result of reduced exposure to sunlight, altered dietary
3
patterns, and exacerbated further by impaired local generation of 1a,25(OH) D .
3
2
In support of these in vitro findings, a large number of epidemiological studies have
identified an association between environments of reduced serum 25(OH)D and
cancer rates.

2.4.2 Dominant Signal Transduction Events

In terms of distribution, evidence is emerging that the normally dynamic flux of the
VDR becomes altered in more transformed and aggressive cancer cells, becoming
restricted to the nucleus [166, 167]. These findings that the normal transport
rates, such as importin-mediated processes, become distorted in malignancy
and may result in a reduced ability for the VDR to sample the cytoplasm for
1a,25(OH) D .
2
3
Reflecting the cooperative and integrated nature of the VDR to function as a
transcription factor, a number of workers have identified mechanisms by which
more dominant signaling process are able either to ablate or attenuate VDR