SerpinA6 Involvement in Prostate Cancer

SerpinA6 参与前列腺癌

• 批准号: 9904589
• 负责人: Sanjeev Shukla
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904589
• 关键词: Affinity; Agonist; Androgen Receptor; Apoptosis Promoter; Apoptotic; Applications Grants; Binding; Binding Sites; Biological; Biological Availability; Biological Models; Cancer Patient; Castration; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell Survival; Cells; Clinical; Cytosol; DNA; Data; Dexamethasone; Dose; Drug resistance; Epithelial Cells; Event; Exclusion; Gene Expression Profile; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Hormones; Human; Implant; In Vitro; Inflammation; Inflammatory; Interleukin-6; Link; Luciferases; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Modeling; Molecular Chaperones; Mus; Neoplasm Metastasis; Nuclear; Nude Mice; PC3 cell line; Pathologic; Patients; Phosphorylation; Phosphotransferases; Plasma; Play; Production; Progesterone; Prostate; Protein Deregulation; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Receptor Activation; Recombinant Proteins; Recombinants; Regulation; Reporting; Research Project Grants; Response Elements; Role; Sampling; Sgk protein; Signal Transduction; Steroids; Therapeutic; Tissues; Transcortin; Western Blotting; castration resistant prostate cancer; cell motility; chromatin immunoprecipitation; clinically relevant; cytokine; glucocorticoid receptor alpha; glucocorticoid-induced orphan receptor; hormone regulation; in vivo Model; mouse model; overexpression; prevent; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer prevention; prostate cancer progression; receptor expression; sarcoma; steroid hormone; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; transgenic adenocarcinoma of mouse prostate; treatment response; tumor

PROJECT SUMMARY Study will determine the potential role of SerpinA6 (Corticosteroid-Binding Globulin; a carrier of glucocorticoids in the plasma) in prostate cancer progression. In castrate resistant prostate cancer (CRPC) patients, presence of higher levels of IL-6 has been observed. Our preliminary data on CRPC prostate cancer cells represented decreasing SerpinA6 levels after IL-6 dose response treatment. Circulatory levels of SerpinA6 believed to keep the steroids inactive and regulate the amount of free hormone acting on target tissues. SerpinA6 contains a single binding site for glucocorticoid (GC) and progesterone, and both binds (80–90%) to SerpinA6 with high affinity. Active role of SerpinA6 is in bioavailability of GC for the glucocorticoid receptor, local delivery, and/or cellular signal transduction of GCs, only the unbound (free) fraction of GCs are biologically active. Moreover reports suggest that SerpinA6 promoter is transcriptionally regulated via the glucocorticoid receptor (GR), this suggest that GR has significant role in SerpinA6 regulation. Increasing GR levels in prostate and increasing IL- 6 level in prostate (due to castration) decreases SerpinA6 expression. Evidence in castrate resistant prostate cancer (CRPC) patients suggests, GR compensates for the lack of androgen receptor (AR) activity in prostate cancer patients. Additionally reports suggest GR has significant role in prostate cancer cells survival and cell cycle regulation. Encouraging preliminary data suggest AR and GR directly or indirectly linked with transcription factor FOXO3a in regulation. We observed increase IL-6 levels in CRPC prostate cancer cells decrease FOXO3a expression. Goal of this research project is to determine the role of SerpinA6 in progression of prostate cancer. Therefore, increased GCs in CRPC patients due to inappropriate SerpinA6 level would increase GR expression in the prostate tissue, which will promote cell survival and proliferation. The proposed mechanistic study, in in-vitro and in-vivo model system will determine whether decrease SerpinA6 levels in CRPC cells have potential to promote prostate cancer progression. Our long term goal is to develop SerpinA6 as potential target for prostate cancer progression, and to determine SerpinA6 modulation as a therapeutic target to inhibit prostate cancer progression. Public Health Significance: There is an immediate need for an effective and clinically relevant target, which has potential role in CRPC progression. We need to have specific and selective targets for progressive events and also need to have the therapeutic approaches to modulate these targets and prevent the further progression of prostate cancer.

项目摘要 研究将确定SerpinA 6（皮质类固醇结合球蛋白;糖皮质激素的载体）的潜在作用 在血浆中）在前列腺癌进展中的作用。在去势抵抗性前列腺癌（CRPC）患者中， IL-6水平升高。我们对CRPC前列腺癌细胞的初步数据代表了 降低IL-6剂量反应治疗后的SerpinA 6水平。SerpinA 6的循环水平被认为可以保持 类固醇失活并调节作用于靶组织的游离激素的量。SerpinA 6包含一个 糖皮质激素（GC）和孕酮的单一结合位点，两者均结合（80-90%）SerpinA 6， 亲和力SerpinA 6的积极作用是在糖皮质激素受体的GC生物利用度、局部递送和/或 在GC的细胞信号转导中，只有GC的未结合（游离）部分具有生物活性。此外 有报道表明SerpinA 6启动子通过糖皮质激素受体（GR）进行转录调节， 提示GR在SerpinA 6调节中具有重要作用。增加前列腺中的GR水平和增加IL- 前列腺中SerpinA 6水平（由于去势）降低SerpinA 6表达。去势抵抗性前列腺的证据 癌症（CRPC）患者的研究表明，GR弥补了前列腺中雄激素受体（AR）活性的缺乏。 癌症患者。此外，报告表明GR在前列腺癌细胞存活和细胞增殖中具有重要作用。 周期调节令人鼓舞的初步数据表明，AR和GR直接或间接与 转录因子FOXO 3a的调控。我们观察到CRPC前列腺癌细胞中IL-6水平增加 降低FOXO 3a的表达。本研究项目的目的是确定SerpinA 6在进展中的作用， 前列腺癌。因此，CRPC患者中由于不适当的SerpinA 6水平而导致的GC增加将 增加前列腺组织中的GR表达，这将促进细胞存活和增殖。拟议 机制研究，在体外和体内模型系统中将确定是否降低SerpinA 6水平， CRPC细胞具有促进前列腺癌进展的潜力。 我们的长期目标是开发SerpinA 6作为前列腺癌进展的潜在靶点，并 确定SerpinA 6调节作为抑制前列腺癌进展的治疗靶点。 公共卫生意义：迫切需要一个有效的和临床相关的目标， 在CRPC进展中具有潜在作用。我们需要为进步活动制定具体且有选择性的目标 还需要有治疗方法来调节这些靶点并防止进一步的 前列腺癌的发展