Page 19 - Vitamin D and Cancer

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E-cadherin by vitamin D enhanced differentiation of colon cancer cells. This in turn
opposed hyperproliferation and thus indicates the importance of vitamin D activity
for normal maintenance of the wnt pathway. It is significant that repression of
E-cadherin and of VDR, and parallel enhanced expression of the transcription fac-
tor SNAIL, was found in patients with aggressive tumor characteristics [47].
CYP27B1 and VDR expression is present also in some prostate and mammary
gland-derived cells, since growth inhibition by 25-(OH)D occurs with concomi-
3
tant upregulation of CYP24A1. If mammary cells are negative for CYP27B1,
there is no mitotic inhibition, and no induction of CYP24A1 expression [48].
When the antimitotic potencies of 25-(OH)D and of 1,25-(OH) D , both in the
3 2 3
nanomolar range, were studied in prostate cells, they were quite similar as long as
cells expressed CYP27B1 [49]. However, it was suggested that during tumor pro-
gression, prostate cells no longer express CYP27B1 [35], though the biological
grade of cells was not established in these studies. Quite similar to colon cells,
EGF stimulated CYP27B1 promoter activity in prostate cell lines via involvement
of the MAPK pathway, at least in those cancer cells that are still differentiated
[50]. In normal human prostatic epithelial cells mitogen-activated protein kinase
phosphatase 5 was induced by 1,25-(OH) D leading to deactivation of protein
2 3
kinase p38 [51]. Activation of p38 and downstream production of interleukin-6
are proinflammatory. Inflammation as well as interleukin-6 overproduction have
been implicated in initiation and progression of prostate as well as of colon cancer
[52]. Similar regulatory networks appear to exist in mammary gland cells (for
review see [53]).

1.2.2 Expression of CYP24A1 During Hyperproliferation
and Tumor Progression

It must be taken into account that the effective tissue concentration of 1,25-(OH) D
3
2
is determined not only by substrate availability but by additional regulatory factors
that may govern also renal vitamin D synthesis: (i) in colonocytes, in prostate and
mammary gland cells, 1,25-(OH) D downregulates CYP27B1 and the VDR (see,
3
2
e.g., [34]); (ii) 1,25-(OH) D at the same time induces CYP24A1-encoded 25-(OH)
2
3
D -24-hydroxylase, the enzyme that initiates stepwise degradation of the hormone;
3
and (iii) at least in colon tumors, expression of CYP24A1 increases dramatically
during progression to a poorly differentiated state (G3-G4) though CYP27B1
expression is diminished [54].
Therefore, one major mechanism for vitamin D resistance or reduced sensitivity
in VDR-positive cancer cells is 1,25-(OH) D catabolism via the C-24 hydroxyla-
2
3
tion pathway. An inverse relation between cellular metabolism of 1,25-(OH) D via
2
3
24-hydroxylation and growth inhibition of prostate cancer cells by vitamin D has
been suggested [55]. A 1,25-(OH) D resistant prostate cell line was growth-
2
3
inhibited when cultured with the active vitamin D metabolite combined with the
CYP24A1 inhibitor liarozole [56]. Colon cells isolated from well-advanced (G3)