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: 6124481
• 负责人: Nancy L. Weigel
• 金额: $ 21.82万
• 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/6124481
• 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比关系 在暴露于阳光之间（这导致了关键的一步 维生素 D 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 细胞受到生物活性物质 1,25-二羟基维生素 D/3 的抑制 维生素 D 的形式。该项目的长期目标是确定 单独使用维生素 D 受体 (VDR) 激动剂还是与维生素 D 受体 (VDR) 激动剂联合使用 其他治疗可用作化学预防或化疗剂 用于前列腺癌。该资助期的目的是： 1. 测试 假设 VDR 激动剂会减少雄激素的生长 体外和体内依赖性和非依赖性前列腺癌细胞 通过 G/1 期细胞的积累并诱导细胞凋亡。我们 发现 LNCaP 人类前列腺癌细胞的治疗可抑制 细胞生长伴随着 G/1 停滞并诱导细胞凋亡。 这一目标将扩大体内研究以及 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 拮抗剂在体外和体内调节前列腺癌细胞生长 体内。由于雄激素消融是晚期前列腺的关键治疗方法 癌症，确定 VDR 激动剂如何与癌症相互作用非常重要 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 期细胞的积累， 诱导细胞凋亡。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因子 积累。我们将确定 Rb 的作用并确定 活性发生改变，导致 Rb 氢磷酸化。我们有 还表明 1,25-二羟基维生素 D/3 诱导细胞凋亡 Bcl-2 和 Bcl/X/L 伴随下调。我们将评估角色 p53、TNFα、神经酰胺生成和 Bcl-2 的调节 回复。