INHIBITION OF PROSTATE CANCER CELL GROWTH BY VITAMIN D

流行病学研究表明， 在暴露于阳光（这导致了在 维生素D的活性形式的合成）和前列腺癌死亡率。 许多研究人员报告说，前列腺癌的生长 细胞被1，25-二羟维生素D/3抑制，生物活性 维生素D的形式。该项目的长期目标是确定 无论是单独的维生素D受体（VDR）激动剂还是与 其它治疗可用作化学预防剂或化学治疗剂 治疗前列腺癌本补助期的目标是：1。测试 假设VDR激动剂会减少雄激素和 依赖性和非依赖性前列腺癌细胞的体外和体内研究 通过细胞在G/1期的积累和诱导细胞凋亡。我们 已经发现LNCaP人类前列腺癌细胞的治疗抑制了 细胞生长伴随G/1停滞和诱导凋亡。 这一目标将扩展体内研究以及 LNCaP细胞的雄激素非依赖性衍生物。2.阐明 VDR激动剂与雄激素受体（AR）激动剂的相互作用， 拮抗剂在体外调节前列腺癌细胞生长和 vivo.由于雄激素消融是晚期前列腺疾病的关键治疗方法， 因此，重要的是确定VDR激动剂如何与 AR配体调节前列腺癌细胞和肿瘤生长。3.确定 VDR激动剂抑制前列腺癌生长的机制 通过细胞在细胞周期的G/1期积累细胞， 诱导细胞凋亡。我们的初步研究表明，Rb是一种 生长抑制反应和细胞周期的关键调节因子 积累我们将确定Rb的作用，并确定 活性的改变导致氢磷酸化Rb。我们有 还显示1，25-二羟基维生素D/3诱导细胞凋亡， Bcl-2和Bcl/X/L表达下调。我们将评估 p53，TNF α，神经酰胺的产生，以及Bcl-2的调节， 反应

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.