Page 68 - Vitamin D and Cancer

3 Anti-inflammatory Activity of Calcitriol in Cancer 55

have shown that calcitriol exerts regulatory effects on some of these inflammatory
networks, revealing important anti-inflammatory actions of calcitriol.

3.3 Anti-inflammatory Effects of Calcitriol

Calcitriol exerts antiproliferative and pro-differentiating effects in many malignant
cells and retards tumor growth in animal models of cancer [1, 17–29]. Several
important mechanisms have been implicated in the anticancer effect of calcitriol
including the induction of cell cycle arrest, stimulation of apoptosis, and inhibition
of metastasis and angiogenesis [1, 20–32]. We used cDNA microarrays as a means
to achieve our research goal of gaining a more complete understanding of the
molecular pathways through which calcitriol mediates its antiproliferative and pro-
differentiation effects in PCa cells [33, 34]. Our results have revealed that calcitriol
regulates the expression of genes involved in PG metabolism and signaling, thereby
reducing the levels and biological activity of PGs [35]. PGs are pro-inflammatory
molecules that promote tumorigenesis and cancer growth [4, 36–39]. We have also
shown that calcitriol up-regulates the expression of mitogen-activated protein
kinase phosphatase-5 (MKP5; also known as dual specificity phosphatase-10
[DUSP10]) and thereby promotes down-stream anti-inflammatory effects, includ-
ing a reduction in the level of expression of pro-inflammatory cytokines [40].
Recent research also indicates that calcitriol interferes with the activation and sig-
naling of nuclear factor-kappaB (NFkB), a transcription factor that regulates the
expression of numerous genes involved in inflammatory and immune responses and
cellular proliferation [41] and thought to play a key role in the process leading from
inflammation to carcinogenesis [42]. In the following sections, we will discuss the
importance of these molecular pathways of inflammation in the development and
progression of PCa, breast cancer (BCa), and colorectal cancer (CRC) and the
therapeutic significance of the inhibition of these of pro-inflammatory signals by
calcitriol.

3.3.1 Regulation of Prostaglandin Metabolism and Signaling

PGs have been shown to play a role in the development and progression of many
cancers and extensive data support the idea that cyclooxygenase-2 (COX-2), the
enzyme responsible for PG synthesis, is an important molecular target in cancer
therapy [4, 36–39]. PGs promote carcinogenesis by stimulating cellular prolifera-
tion, inhibiting apoptosis, promoting angiogenesis, and by activating carcinogens
[43, 44]. We have recently discovered that calcitriol regulates the expression of
several key genes involved in the PG pathway causing a decrease in PG synthesis,
an increase in PG catabolism, and the inhibition of PG signaling through their
receptors in PCa cells [35].