INHIBITION OF PROSTATE CANCER CELL GROWTH BY VITAMIN D

流行病学研究表明，两者之间存在相反的关系 在暴露在阳光下(这导致了 维生素D活性形式的合成)和前列腺癌死亡率。 一些研究人员报告说，前列腺癌的生长 细胞受到生物活性1，25-二羟基维生素D/3的抑制 维生素D的形式这个项目的长期目标是确定 无论是维生素D受体(VDR)激动剂单独使用还是与 其他治疗方法也可用作化学预防或化疗药物。 治疗前列腺癌。这一授权期的目的是：1.测试 VDR激动剂将减少两种雄激素生长的假说 依赖和非依赖性前列腺癌细胞的体内外研究 通过G/1期细胞积聚和诱导细胞凋亡。我们 已发现治疗LNCaP的人前列腺癌细胞抑制 细胞生长伴随G/1期停滞，并诱导细胞凋亡。 这一目标将扩大体内研究以及对 LNCaP细胞的雄激素非依赖性衍生物。2.澄清 维生素D受体激动剂与雄激素受体激动剂的相互作用 拮抗剂在调节前列腺癌细胞生长中的作用 活着。因为雄激素消融术是晚期前列腺癌的关键治疗方法 癌症，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 通过在细胞周期的G/1期积累细胞和 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的角色以及确定 活性发生改变，导致氢化Rb。我们有 还表明，1，25-二羟基维生素D/3诱导细胞凋亡和 随之而来的是Bcl2和BclX/L的下调，我们将评估其作用 抑癌基因p53、肿瘤坏死因子α、神经酰胺的产生及对Bcl-2的调控 回应。

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.