PTH-related peptide and vit D in prostate cancer growth

PTH 相关肽和维生素 D 在前列腺癌生长中的作用

• 批准号: 7238861
• 负责人: MIRIAM FALZON
• 金额: $ 25.77万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-07 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238861
• 关键词: PTH; related; peptide; vit; prostate

DESCRIPTION (provided by applicant): Prostate cancer is the largest cause of male cancer death in the United States; many prostate cancer patients have metastatic disease at diagnosis. Vitamin D deficiency is a risk factor for prostate cancer, and 1,25-dihydroxyvitarhin D3 (1,250, the hormonally active form of vitamin D) and noncalcemic analogues have shown therapeutic benefits in clinical trials with prostate cancer patients. Prostate cancer cells produce many growth factors, including parathyroid hormone-related protein (formerly peptide, PTHrP). We show that PTHrP overexpression increases prostate cancer cell (a) proliferation; (b) adhesion to the extracellular matrix proteins collagen types I and IV, laminin, and fibronectin; (c) migration onto laminin and collagen type I; (d) invasion of Matrigel, a reconstituted basement membrane; (e) anchorage-independent cell growth; (f) cell surface expression of the pro-invasive integrin a6|34; and (g) xenograft growth in vivo. 1,250 exerts opposite effects on all these parameters, and downregulates PTHrP gene expression. Both PTHrP and integrin 04 expression are required for the anti-proliferative and anti-invasive effects of 1,250, as shown using siRNAs. We thus hypothesize that (a) PTHrP facilitates prostate cancer metastasis by upregulating pro-invasive integrin expression, and (b) the therapeutic benefits of vitamin D are mediated via both downregulatipn of PTHrP gene expression and a direct effect on integrin expression. This project seeks to understand the relationship between PTHrP, vitamin D and integrin a6p4 in prostate cancer cells, by pursuing three Aims. (1) The pathways via which PTHrP and vitamin D regulate integrin a634 expression will be investigated using siRNAs and integrin promoter deletions/transient transfection assays. Since integrin a6(34 increases cancer aggressiveness, we will determine by immunoprecipitation whether vitamin D alters the association of a6 from (34 to 31. (2) The role of PTHrP and integrin (34 in prostate cancer cell growth and bone metastasis, and the effect of concomitant vitamin D treatment, will be studied in vivo using a nude mouse model. (3) The vitamin D response elements via which vitamin D regulates PTHrP gene expression will be identified by PTHrP gene promoter deletions and transient transfection assays. Understanding the relationship between PTHrP, vitamin D, and pro-invasive integrin expression, and the molecular pathways involved, should lead to the development of new combinatorial therapeutic approaches to manage prostate cancer.

描述（由申请人提供）：前列腺癌是美国男性癌症死亡的最大原因；许多前列腺癌患者在诊断时患有转移性疾病。维生素D缺乏症是前列腺癌的危险因素，1,25-二羟基羟基葡萄酒D3（1,250，维生素D的荷尔蒙活性形式）和非钙血症类似物显示出与前列腺癌患者的临床试验中的治疗益处。前列腺癌细胞产生许多生长因子，包括甲状旁腺激素相关蛋白（以前是肽，PTHRP）。我们表明，PTHRP的过表达增加了前列腺癌细胞（A）增殖。 （b）对细胞外基质蛋白胶原蛋白I和IV，层粘连蛋白和纤连蛋白的粘附； （c）迁移到层粘连蛋白和I型胶原蛋白上； （d）入侵Matrigel，一个重构的地下室膜； （e）独立的细胞生长； （f）促侵入性整合素A6 | 34的细胞表面表达； （g）体内异种移植生长。 1,250对所有这些参数产生相反的影响，并下调PTHRP基因表达。如使用siRNA所示，PTHRP和整合素04表达都是1,250的抗增殖和抗侵入性作用所必需的。因此，我们假设（a）PTHRP通过上调促侵入性整联蛋白表达来促进前列腺癌转移，并且（b）通过PTHRP基因表达的下调和对整合素表达的直接作用，维生素D的治疗益处均可介导。该项目试图通过追求三个目标来了解前列腺癌细胞中PTHRP，维生素D和整合素A6P4之间的关系。 （1）将使用siRNA和整联蛋白启动子缺失/瞬态转染测定法调节PTHRP和维生素D调节整联蛋白A634表达的途径。由于整联蛋白A6（34增加了癌症的侵略性，我们将通过免疫沉淀来确定维生素D是否将A6的关联从（34到34至31。 D调节PTHRP基因表达将通过PTHRP基因启动子缺失和瞬时转染测定法。