VITAMIN D AND INHIBITION OF PROSTATE CANCER CELL GROWTH

维生素 D 与抑制前列腺癌细胞生长

• 批准号: 6294010
• 负责人: LaMonica Vanette Stewart
• 金额: $ 4.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6294010
• 关键词: 1,25 dihydroxycholecalciferol; androgen receptor; androgens; antisense nucleic acid; apoptosis; athymic mouse; autocrine; binding proteins; hormone regulation /control mechanism; hormone related neoplasm /cancer; insulinlike growth factor; male; metastasis; microarray technology; neoplasm /cancer nutrition therapy; neoplastic growth; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; oligonucleotides; prostate neoplasms; vitamin D; vitamin D receptors; vitamin analog; vitamin therapy; 1,25 dihydroxycholecalciferol; androgen receptor; androgens; antisense nucleic acid; apoptosis; athymic mouse; autocrine; binding proteins; hormone regulation /control mechanism; hormone related neoplasm /cancer; insulinlike growth factor; male; metastasis; microarray technology; neoplasm /cancer nutrition therapy; neoplastic growth; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; oligonucleotides; prostate neoplasms; vitamin D; vitamin D receptors; vitamin analog; vitamin therapy

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.

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（1,25D）已被证明可以抑制雄激素依赖性和雄激素独立的前列腺癌细胞系的生长。但是，尚不完全了解1,25D暴露导致前列腺癌细胞生长降低的机制。还不清楚在雄激素依赖性和雄激素独立肿瘤中表达的雄激素受体（AR）是否会影响前列腺癌对1,25D和其他维生素D受体（VDR）激动剂反应的能力。我的假设是1）1）1,25D诱导的生长抑制并不需要AR，而2）生长抑制是由自分泌生长因子信号传导改变而介导的。该项目的目的是通过检查AR和自分泌生长因子在1,25D刺激的生长抑制中的作用来检验这一假设。在AIM 1下，我将通过测试VDR激动剂在表达非常低的AR水平的LNCAP细胞中的测试效果，探索AR在1,25D诱导的生长抑制中的重要性。 AIM 2下的实验将通过首先探索1,25D的生长抑制是否需要上调IGF结合蛋白3来检查自分泌生长因子在1,25D生长抑制中的作用。此外，蛋白质组学和DNA微阵列分析将用于识别介导1,25D诱导的生长抑制的其他生长因子信号传导系统。 AIM 3将使用裸小鼠异种移植模型来检查VDR激动剂对雄激素非依赖性前列腺肿瘤在体内生长的影响。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，将获得信息，以进一步了解VDR激动剂调节前列腺癌细胞生长的机制以及VDR激动剂作为前列腺癌的化学治疗剂的价值。