Several population studies suggest that higher dietary calcium, at intake levels suggested for optimal bone health, is associated with an increased risk of aggressive prostate cancer. This may be due to reduced renal synthesis of 1,25 dihydroxyvitamin D (1,25(OH)2 D), a hormonally active form of vitamin D that acts through the nuclear vitamin D receptor (nVDR) to suppress prostate cell growth, promote differentiation, and stimulate apoptosis. Other epidemiologic studies support the hypothesis that low vitamin D stores are associated with increased prostate cancer risk. Studies in vitro show that prostate cells can convert 25-OH D into 1,25(OH)2 D. While a role for dietary modulation of vitamin D metabolite levels in prostate cancer prevention can be inferred by combining data from population and cell studies, demonstration of this phenomenon in a controlled, in vivo setting represents a significant gap in the field of prostate cancer prevention. Our hypothesis is that high vitamin D status (i.e. high serum 25-OH D) and high serum 1,25(OH)2 D protect against prostate cancer by activating genetic programs through the nVDR. We believe that dietary factors like high calcium intake will suppress the protective effect of serum 1,25(OH)2 D but not of elevated 25-OH D levels.
The specific aims of the application are to: (1) Establish the relationship between dietary calcium and vitamin D intake and the protective role of serum 25-OH D and 1,25(OH)2D against prostate cancer in Wistar-Unilever rats during NMU-androgen-induced prostate carcinogenesis, (2) Establish the role of dietary calcium and vitamin D on androgen-induced proliferation and apoptosis and on protective patterns of gene expression in the prostate epithelium, and (3) Evaluate the consequence of nVDR deletion and 1alpha hydroxylase over-expression in prostate-specific IGF-1 transgenic mice predisposed to prostate carcinogenesis. In our studies we will examine stepwise carcinogenesis (PIN, carcinoma in situ, adenocarcinoma), quantitate relevant serum biomarkers, and assess expression of vitamin D sensitive proteins and genes in prostate tissue to provide insight into mechanisms whereby dietary calcium and vitamin D modulate prostate carcinogenesis through the vitamin D axis. These data will provide us with the mechanistic basis for dietary recommendations to prevent prostate cancer and optimize bone health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101113-04
Application #
7236159
Study Section
Special Emphasis Panel (ZCA1-SRRB-D (J2))
Program Officer
Kim, Young Shin
Project Start
2004-07-13
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$443,393
Indirect Cost
Name
Purdue University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Fleet, James C; DeSmet, Marsha; Johnson, Robert et al. (2012) Vitamin D and cancer: a review of molecular mechanisms. Biochem J 441:61-76
Kovalenko, Pavlo L; Zhang, Zhentao; Yu, Jun-Ge et al. (2011) Dietary vitamin D and vitamin D receptor level modulate epithelial cell proliferation and apoptosis in the prostate. Cancer Prev Res (Phila) 4:1617-25
Maund, Sophia L; Barclay, Wendy W; Hover, Laura D et al. (2011) Interleukin-1? mediates the antiproliferative effects of 1,25-dihydroxyvitamin D3 in prostate progenitor/stem cells. Cancer Res 71:5276-86
Kovalenko, Pavlo L; Zhang, Zhentao; Cui, Min et al. (2010) 1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1. BMC Genomics 11:26
Zhang, Zhentao; Kovalenko, Pavlo; Cui, Min et al. (2010) Constitutive activation of the mitogen-activated protein kinase pathway impairs vitamin D signaling in human prostate epithelial cells. J Cell Physiol 224:433-42
Xue, Yingben; Fleet, James C (2009) Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 136:1317-27, e1-2
Li, Jia; Fleet, James C; Teegarden, Dorothy (2009) Activation of rapid signaling pathways does not contribute to 1 alpha,25-dihydroxyvitamin D3-induced growth inhibition of mouse prostate epithelial progenitor cells. J Cell Biochem 107:1031-6
Fleet, James C (2008) Molecular actions of vitamin D contributing to cancer prevention. Mol Aspects Med 29:388-96
Fleet, James C; Gliniak, Christy; Zhang, Zhentao et al. (2008) Serum metabolite profiles and target tissue gene expression define the effect of cholecalciferol intake on calcium metabolism in rats and mice. J Nutr 138:1114-20
Rowling, Matthew J; Gliniak, Christy; Welsh, JoEllen et al. (2007) High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice. J Nutr 137:2608-15

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