VITAMIN D AND INHIBITION OF PROSTATE CANCER CELL GROWTH

前列腺癌是影响美国男性的主要健康问题之一。1，25-二羟基维生素D3（1，25 D）已被证明抑制雄激素依赖性和雄激素非依赖性前列腺癌细胞系的生长。然而，1，25 D暴露导致前列腺癌细胞生长减少的机制尚未完全了解。雄激素受体（AR）在雄激素依赖性和雄激素非依赖性肿瘤中表达，是否影响前列腺癌对1，25 D和其他维生素D受体（VDR）激动剂的反应能力也不清楚。我的假设是：1）AR不是1，25 D诱导的生长抑制所必需的，2）生长抑制是由自分泌生长因子信号转导的改变介导的。本项目的目的是通过检测AR和自分泌生长因子在1，25 D刺激的生长抑制中的作用来验证这一假设。在目标1下，我将通过测试VDR激动剂在表达非常低AR水平的LNCaP细胞中的作用来探索AR在1，25 D诱导的生长抑制中的重要性。目标2下的实验将通过首先探索1，25 D的生长抑制是否需要IGF结合蛋白-3的上调来检查自分泌生长因子在1，25 D生长抑制中的作用。此外，蛋白质组学和DNA微阵列分析将用于确定其他生长因子信号系统介导的1，25 D诱导的生长抑制。目的3将使用裸鼠异种移植模型来检查VDR激动剂对体内雄激素非依赖性前列腺肿瘤生长的作用。此外，这些研究将探讨循环雄激素水平或肿瘤位置是否影响肿瘤对VDR激动剂的反应。从拟议的研究中，将获得的信息，将提供进一步了解的机制，VDR激动剂调节前列腺癌细胞生长和VDR激动剂作为化疗药物的前列腺癌的价值。

Prostate cancer is one of the major health problems affecting American males. 1,25-dihydroxyvitamin D3 (1,25D), has been demonstrated to inhibit growth of both androgen-dependent and androgen-independent prostate cancer cell lines. However, mechanisms by which 1,25D exposure leads to decreases in prostate cancer cell growth are not fully understood. It is also not clear whether androgen receptor (AR), which is expressed in both androgen-dependent and androgen-independent tumors, affects the ability of prostate cancer to respond to 1,25D and other vitamin D receptor (VDR) agonists. It is my hypothesis that 1) AR is not required for 1,25D-induced growth inhibition, and 2) growth inhibition is mediated by alterations in autocrine growth factor signaling. The goal of this project is to test this hypothesis by examining the role of AR and autocrine growth factors in 1,25D stimulated growth inhibition. Under Aim 1, I will explore the importance of AR in 1,25D-induced growth inhibition by testing effects of VDR agonists in LNCaP cells that express very low AR levels. The experiments under Aim 2 will examine the role of autocrine growth factors in 1,25D growth repression by first exploring whether growth inhibition by 1,25D requires upregulation of IGF binding protein-3. In addition, proteomics and DNA microarray analysis will be used to identify other growth factor signaling systems that mediate 1,25D-induced growth inhibition. Aim 3 will use a nude mouse xenograft model to examine the effect of VDR agonists on androgen-independent prostate tumor growth in vivo. In addition, these studies will explore whether circulating androgen levels or tumor location affect tumor response to VDR agonists. From the proposed studies, information will be gained that will provide further insight into the mechanisms by which VDR agonists regulate prostate cancer cell growth and the value of VDR agonists as chemotherapeutic agents for prostate cancer.