INHIBITION OF PROSTATE CANCER CELL GROWTH BY VITAMIN D

维生素 D 抑制前列腺癌细胞生长

• 批准号: 2765358
• 负责人: Nancy L. Weigel
• 金额: $ 22.41万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-24 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2765358
• 关键词: 1,25 dihydroxycholecalciferol; BCL2 gene /protein; androgen inhibitor; androgen receptor; angiogenesis inhibitors; apoptosis; athymic mouse; cell cycle; cell growth regulation; cell line; cell proliferation; chemoprevention; cyclin dependent kinase; flow cytometry; gene expression; genetic transcription; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; northern blottings; p53 gene /protein; prostate neoplasms; retinoblastoma protein; tumor necrosis factor alpha; vitamin D receptors; vitamin analog

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.

流行病学研究表明存在反向关系 在暴露于阳光之间（这导致了一个关键的步骤 维生素D）和前列腺癌死亡率的活性形式的合成。 许多研究人员报告说，前列腺癌的生长 细胞被1,25-二羟基维生素D/3抑制，生物活性 维生素D的形式D。该项目的长期目标是确定 是单独使用维生素D受体（VDR）激动剂还是与 其他处理可作为化学预防或化学治疗剂 前列腺癌。本赠款期的目的是：1。测试 假设VDR激动剂将减少两种雄激素的生长 依赖和独立的前列腺癌细胞在体外和体内 通过g/1中细胞的积累和凋亡的诱导。我们 发现LNCAP人前列腺癌细胞的治疗抑制 细胞生长，随附的g/1停滞和凋亡诱导。 这个目标将扩展体内研究的研究以及 LNCAP细胞的雄激素独立衍生物。 2。阐明 VDR激动剂与雄激素受体（AR）激动剂的相互作用和 在调节前列腺癌细胞生长体外和在内的拮抗剂 体内。由于雄激素消融是晚期前列腺的关键疗法 癌症，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期间积累细胞的细胞，并 诱导凋亡。我们的初步研究表明RB是 生长抑制反应和细胞周期的关键调节剂 积累。我们将确定RB的作用，并确定 改变导致水磷酸化的RB的活性。我们有 还表明1,25-二羟基维生素D/3诱导凋亡和 伴随Bcl-2和Bcl/X/L的下调。我们将评估角色 p53，tnfalpha，神经酰胺生成和Bcl-2的调节 回复。