Epidemiological studies suggest that there is an inverse relationship between exposure to sunlight (which induces a critical step in the synthesis of the active form of vitamin D) and prostate cancer mortality. A number of investigators have reported that the growth of prostate cancer cells is inhibited by 1,25-dihydroxyvitamin D/3, the biologically active form of vitamin D. The long term goals of this project are to determine whether a vitamin D receptor (VDR) agonist alone or in combination with other treatments is useful as a chemopreventive or chemotherapeutic agent for prostate cancer.
The aims of this grant period are: 1. To test the hypothesis that VDR agonists will reduce the growth of both androgen dependent and independent prostate cancer cells in vitro and in vivo through an accumulation of cells in G/1 and induction of apoptosis. We have found that treatment of LNCaP human prostate cancer cells inhibits cell growth with an accompanying G/1 arrest and induction of apoptosis.
This aim will extend the studies in vivo studies as well as to studies of androgen independent derivatives of LNCaP cells. 2. Elucidate the interactions of VDR agonists with androgen receptor (AR) agonists and antagonists in regulating prostate cancer cell growth in vitro and in vivo. Since androgen ablation is a key treatment for advanced prostate cancer, it will be important to determine how VDR agonists interact with AR ligands to regulate prostate cancer cell and tumor growth. 3. Determine the mechanisms by which VDR agonists inhibit the growth of prostate cancer cells through accumulation of cells in the G/1 phase of the cell cycle and induction of apoptosis. Our preliminary studies suggest that Rb is a critical regulator of the growth inhibitory response and cell cycle accumulation. We will determine the role of Rb as well as identifying the activities which are altered resulting in hydrophosphorylated Rb. We have also shown that 1,25-dihydroxyvitamin D/3 induces apoptosis and concomitant down-regulation of Bcl-2 and Bcl/X/L. We will assess the roles of p53, TNFalpha, ceramide generation, and regulation of Bcl-2 in this response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075337-03
Application #
6328985
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Kim, Young Shin
Project Start
1998-12-24
Project End
2003-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
3
Fiscal Year
2001
Total Cost
$226,060
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Stewart, Lamonica V; Weigel, Nancy L (2005) Role of insulin-like growth factor binding proteins in 1alpha,25-dihydroxyvitamin D(3)-induced growth inhibition of human prostate cancer cells. Prostate 64:9-19
Stewart, LaMonica V; Lyles, Besstina; Lin, Ming-Fong et al. (2005) Vitamin D receptor agonists induce prostatic acid phosphatase to reduce cell growth and HER-2 signaling in LNCaP-derived human prostate cancer cells. J Steroid Biochem Mol Biol 97:37-46
Murthy, Shalini; Agoulnik, Irina U; Weigel, Nancy L (2005) Androgen receptor signaling and vitamin D receptor action in prostate cancer cells. Prostate 64:362-72
Polek, Tara C; Stewart, LaMonica V; Ryu, Elizabeth J et al. (2003) p53 Is required for 1,25-dihydroxyvitamin D3-induced G0 arrest but is not required for G1 accumulation or apoptosis of LNCaP prostate cancer cells. Endocrinology 144:50-60
Murthy, Shalini; Marcelli, Marco; Weigel, Nancy L (2003) Stable expression of full length human androgen receptor in PC-3 prostate cancer cells enhances sensitivity to retinoic acid but not to 1alpha,25-dihydroxyvitamin D3. Prostate 56:293-304
Polek, Tara C; Weigel, Nancy L (2002) Vitamin D and prostate cancer. J Androl 23:9-17
Blutt, S E; Polek, T C; Stewart, L V et al. (2000) A calcitriol analogue, EB1089, inhibits the growth of LNCaP tumors in nude mice. Cancer Res 60:779-82
Blutt, S E; McDonnell, T J; Polek, T C et al. (2000) Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. Endocrinology 141:7-Oct