Page 28 - Vitamin D and Cancer

1 Vitamin D: Synthesis and Catabolism 15

Genistein could also have anti-inflammatory properties in the colon: When mice
were fed 0.04% dietary calcium, COX-2 mRNA and protein were increased two-
fold in the female colon mucosa and to a lesser extent in males. Supplementation
of genistein to the diet lowered COX-2 expression to control levels (0.5% dietary
calcium) in both genders [104]. This suggests that genistein could have a beneficial
effect on colonic inflammation similar to that seen with 17b-estradiol in the human
pilot study described before (Sect. 1.2.3). Since genistein preferentially activates
ER-b [105, 106], which is equally expressed in the colon of women and men, low
rates of colorectal cancer incidence in both genders in soy-consuming populations
could be due to appropriate modulation of the anti-inflammatory and anticancer
potential of vitamin D by phytoestrogens.
Also the human prostate is frequently affected by inflammatory disease, which
could predispose to development of malignancies. Since the inflammation-related
prostaglandin pathway is negatively affected in prostate cancer cells by genistein
[107], this suggests a potential mechanism of prostate cancer prevention in soy-
consuming countries. Experimental data from Farhan et al. indicated that genistein
very efficiently reduced the activity of CYP24A1 in human prostate cancer cells
[57, 108], probably by direct binding to the CYP24A1 protein [58]. In contrast to
the colon, genistein inhibited CYP27B1 mRNA expression in prostate cells, and
this may involve histone deacetylation since trichostatin A rescues CYP27B1 from
transcriptional inactivation [58] (see also [95]). Treatment of prostate cancer cells
with 1,25-(OH) D together with genistein potentiated the antimitotic activity of the
2 3
active metabolite. This suggests an increased half-life of 1,25-(OH) D due to inhi-
2 3
bition of CYP24A1 activity [109], as already indicated in previous studies [58].

1.3.3 Effect of Folate on CYP24A1 Expression

Folate, a water-soluble vitamin of the B family, is essential for synthesis, repair, and
methylation of DNA. As a methyl donor, folate could play an important role in
epigenetic regulation of gene expression. While folic acid was supplemented to
foods in the USA in the late 1990s to curb incidence of neural tube defects, and
blood folate concentrations increased in the survey period shortly thereafter, there
has been a decline since and its causes are unknown [110].
Sporadic cancers evolve over a lifetime and could therefore be at least equally
affected by low folic acid intake as neural tube development. Older age and inad-
equate folate intake lead to altered methylation patterns [111]. Evidence is increas-
ing that a low folate status predisposes to development of several common
malignancies including colorectal cancer [112]. Giovannucci et al. [113] and others
demonstrated that prolonged intake of folate above currently recommended levels
significantly reduced the risk of colorectal cancer.
To investigate the relevance of folate for regulation of the vitamin D system, we
used C57/BL6 mice on the semisynthetic AIN76A diet, which contained, among oth-
ers, 5% fat, 0.025 mg/g vitamin D , 5 mg/g calcium, and 2 mg/g folic acid [114, 115].
3