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.
