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PhD Dissertation - Local production of active vitamin D inhibits Prostate Cancer – Oct 2012

Mechanism(s) by which vitamin D and its metabolites inhibit prostate cancer growth

Banks, Mara E., Ph.D., BOSTON UNIVERSITY, 2012, 195 pages; 3529038

Prostate cancer cells contain vitamin D receptor for 1?,25-dihydroxyvitamin D3 [1?,25(OH)2D3], which is known to inhibit the proliferation and invasiveness of these cells. Normal prostate cells and several prostate cancer cell lines convert 25-hydroxyvitamin D 3 [25(OH)D3] to 10,25(OH)2D3. In addition, epidemiological evidence correlated an inverse relationship between vitamin D status and prostate cancer risk, suggesting that vitamin D and its metabolism may be important in the development and growth of prostate cancer. Using a human androgen-insensitive prostate cancer xenograft mouse model, the effect(s) of dietary vitamin D and calcium on tumor growth were evaluated. DU-145 cells were implanted in mice and monitored for 76 days. Serum, for 25(OH)D and calcium determinations, and tumors, for immunohistochemistry and gene expression analysis, were collected.

Tumor growth was highest in mice fed a normal calcium, vitamin D deficient diet.

Diets containing high calcium, with or without vitamin D, did not alter tumor growth compared to the normal calcium vitamin D sufficient diet.

To elucidate the role of 1?,25(OH)2D3 production by 25-hydroxyvitamin D-1?-hydroxylase (CYP27131) on prostate cancer cell growth, LNCaP cells were stably transfected with CYP27B1 (1?-S cells). 1?-S cells converted 25(OH)D 3 to 1?,25(OH)2D3 unlike untransfected LNCaP cells.

There was a dose dependent decrease in 3H-thymidine incorporation in 1?,25(OH)2D3 treated LNCaP cells, not seen with 25(OH)D3 treatment, and in 1?-S cells treated with 25(OH)D3. In DU-145 cells, the decrease in 3H-thymidine incorporation seen with 25(OH)D3 treatment was diminished with suppression of CYP2781 with siRNA. 1?,25(OH)2 D3 treated LNCaP cells and 25(OH)D3 treated 1?-S cells demonstrated increased G1 phase accumulation and apoptosis while 25(OH)D3 treatment had no effect in LNCaP cells.

1?,25(OH) 2D3, but not 25(OH)D3, in LNCaP cells and 25(OH)D 3 in l?-S cells increased cell cycle regulatory gene expression; CDKN1A, CDKNIB and TP53, and opposing apoptotic genes, BAX and BCL-2, were induced and suppressed, respectively. 25-hydroxyvitamin D-24-hydroxylase (24-OHase) suppression enhanced 25(OH)D3 and 1?,25(OH)2D 3 effects in LNCaP and l?-S cells.

This study supports the hypothesis that local production of 1?,25(OH)2D is important to inhibiting prostate cancer growth and suggests dietary vitamin D as a preventive agent in androgen-insensitive prostate cancer.
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