Page 75 - Vitamin D and Cancer

62 A.V. Krishnan and D. Feldman

and activates the transcription of pro-inflammatory cytokines, chemokines, and
anti-apoptotic factors [104]. In contrast to normal cells many cancer cells have
elevated levels of active NFkB [105, 106]. Constitutive activation of NFkB has
been observed in androgen-independent PCa [107–109]. The NFkB protein RelB
is uniquely expressed at high levels in PCa with high Gleason scores [110]. NFkB
plays a major role in the control of immune responses and inflammation and pro-
motes malignant behavior by increasing the transcription of the anti-apoptotic gene
Bcl2 [111], cell cycle progression factors such as c-myc and cyclin D1, proteolytic
enzymes such as matrix metalloproteinase 9 (MMP-9), urokinase-type plasmino-
gen activator (uPA), and angiogenic factors such as VEGF and interleukin-8 (IL-8)
[109, 112]. IL-8, an angiogenic factor and a downstream target of NFkB, is also a
potent chemotactic factor for neutrophils and is associated with the initiation of the
inflammatory response [113].
Calcitriol is known to directly modulate basal and cytokine-induced NFkB
activity in many cells including human lymphocytes [114], fibroblasts [115],
and peripheral blood monocytes [116]. A reduction in the levels of the NFkB
inhibitory protein IkBa has been reported in mice lacking the VDR [117].
IKKb-mediated activation of NFkB contributes to the development of colitis-
associated cancer through the activation of anti-apoptotic genes and the produc-
tion IL-6 [42]. Addition of a VDR antagonist to colon cancer cells upregulates
NFkB activity by decreasing the levels of IkBa, suggesting that vitamin D
ligands exert a suppressive effect on NFkB activation [118]. Calcitriol and its
analogs have been shown to block NFkB activation by increasing the expression
of IkB in macrophages and peripheral blood mononuclear cells [116, 119, 120].
There is considerable evidence for the inhibition of NFkB signaling by calcitriol
in PCa cells. Calcitriol decreases the levels of the angiogenic and pro-inflamma-
tory cytokine IL-8 in immortalized normal human prostate epithelial cell lines
(HPr-1 and RWPE-1) and established PCa cell lines (LNCaP, PC-3 and DU145)
[121]. The suppression of IL-8 by calcitriol appears to be due to the inhibition
of NFkB signaling. Calcitriol reduces the nuclear translocation of the NFkB
subunit p65 thereby inhibiting the NFkB complex from binding to its DNA
response element and consequently suppressing the NFkB stimulation of tran-
scription of downstream targets such as IL-8 [121]. Thus calcitriol could delay
the progression of PCa by suppressing the expression of angiogenic and pro-
inflammatory factors such as VEGF and IL-8. In addition, calcitriol also indi-
rectly inhibits NFkB signaling by up-regulating the expression of IGFBP-3,
which has been shown to interfere with NFkB signaling in PCa cells by sup-
pressing p65 NFkB protein levels and the phosphorylation of IkBa [122]. NFkB
also provides an adaptive response to PCa cells against cytotoxicity induced by
redox-active therapeutic agents and is implicated in radiation resistance of can-
cers [123, 124]. A recent study shows that calcitriol significantly enhances the
sensitivity of PCa cells to ionizing radiation by selectively suppressing
radiation-mediated RelB activation [125]. Thus calcitriol may serve as an effec-
tive agent for sensitizing PCa cells to radiation therapy via suppression of the
NFkB pathway.