Page 161 - Vitamin D and Cancer

148 E. Gocek and G.P. Studzinski

One mechanism that can explain the reduced cell proliferation which accompanies
differentiation is the marked inhibitory effect of 1,25D on the expression of epidermal
growth factor receptor (EGFR), apparent at both mRNA and protein levels in
CaCo-2 cells [32]. The accumulated data also suggest that the central role in
1,25D-induced differentiation is played by the vitamin D receptor (VDR). An early
study demonstrated that 1,25D has a protective effect on chemically induced rat
colon carcinogenesis [33], and others showed that VDR can be a marker for colon
cancer cell differentiation [34, 35]. This was followed up by Cross and colleagues
in a series of experiments which showed that VDR levels increased in early stages
of carcinogenesis, or in human colonic mucosa during early tumor development,
but that VDR levels were low in poorly differentiated late-stage carcinomas
[36, 37]. This suggested that VDR levels have a restraining effect on the growth of
colon cells. A mechanism that can explain the increased levels of VDR in differen-
tiated colon cells was provided by the Brasitus group, indicating that in CaCo-2
cells 1,25D causes an increased activity of the AP-1 transcription factor [27], which
is downstream from the mitogen-activated protein kinases (MAPK) pathways and
can transactivate VDR gene expression [38]. The consequent up-regulation of VDR
may further be increased in the presence of 1,25D by stabilization of the VDR
protein [39], but the nature of the initial activation of MAPK pathways in colon
cancer cells is not entirely clear. The suggested calcium-induced activation of
protein kinase C alpha (PKC a) as an upstream event in MAPK activation [27, 40]
appears to be feasible, as an influx of calcium into the cells is known to occur after
1,25D exposure of many types of cells including colon cancer [41], but this path-
way remains to be further investigated. Nonetheless, the importance of VDR in
colon cancer cell differentiation is further underscored by the suggestion that
butyrate-induced differentiation of CaCo-2 cells is mediated by VDR [42], and by
the recent report that decreased recruitment of VDR to the vitamin D response ele-
ments (VDRE) contributes to the reduced transcriptional responsiveness of prolif-
erating CaCo-2 cells to 1,25D [43].
An emerging role for VDR, other than its function as a transcription factor that
binds to VDRE in the promoter regions of 1,25D-responsive genes, is exemplified
by the finding that VDR can interact with b-catenin, and thereby repress in colon
cells the oncogenic gene-regulatory activity of b-catenin [29]. The transrepression
of b-catenin signaling is not limited to an interaction with VDR, as such interactions
can take place with other nuclear receptors, such as the retinoic acid receptor (RAR)
and the androgen receptor (AR) [29, 44]. This interaction has been shown to involve
also the coactivator p300, a histone acetyl transferase [45]. The recently reported
repression of the VDR gene by the transcription factor SNAIL [46], and the repression
by 1,25D of the Wingless-related MMTV integration site (Wnt) antagonist
DICKOPF-4 [47] may also be important for the inhibition of Wnt/b-catenin signaling
by 1,25D, and for its induction of differentiation in colon cancer cells.
Signaling by b-catenin can also be repressed by the 1,25D-induced up-regulation
of the expression of E-cadherin [29], a transmembrane protein that plays a major
role in the maintenance of the adhesive and polarized phenotype of epithelial cells
[48]. The presence of E- cadherin can promote nuclear export of b-catenin, and this