SerpinA6 Involvement in Prostate Cancer

项目总结 研究将确定SerpinA6(皮质类固醇结合球蛋白；糖皮质激素的载体)的潜在作用 在前列腺癌进展中)。在去势抵抗前列腺癌(CRPC)患者中， 已经观察到较高水平的IL-6。我们关于CRPC前列腺癌细胞的初步数据代表 IL-6剂量反应治疗后降低血清A6水平。循环中血清A6水平被认为保持在 类固醇不起作用，并调节作用于靶组织的游离荷尔蒙的量。SerpinA6包含一个 糖皮质激素(GC)和孕酮的单一结合部位，两者都与SerpinA6结合(80%-90%)，且高 亲和力。SerpinA6在GC对糖皮质激素受体的生物利用度、局部给药和/或 GCs的细胞信号转导，只有非结合(游离)部分的GCs具有生物学活性。更有甚者 有报道表明，SerpinA6启动子是通过糖皮质激素受体(GR)转录调节的。 提示GR在SerpinA6的调节中具有重要作用。增加前列腺糖皮质激素受体水平和增加IL-2 6在前列腺中的水平(由于去势)降低了SerpinA6的表达。抗去势前列腺癌的证据 癌症(CRPC)患者认为，GR补偿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生长中具有重要作用。 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FOXO3a参与调控。我们观察到CRPC前列腺癌细胞中IL-6水平升高 减少FOXO3a的表达。本研究项目的目标是确定SerpinA6在疾病进展中的作用 前列腺癌。因此，CRPC患者由于血清A6水平不当而导致的GCs增加将 增加前列腺组织中GR的表达，这将促进细胞的存活和增殖。建议数 在体外和体内模型系统中的机制研究将确定是否降低血清A6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SerpinA6作为前列腺癌进展的潜在靶点，并 确定SerpinA6调节作为抑制前列腺癌进展的治疗靶点。 公共卫生意义：迫切需要一个有效和临床相关的目标， 在CRPC的进展中具有潜在的作用。我们需要对进步事件有具体和有选择性的目标 还需要有治疗方法来调节这些靶点并防止进一步的 前列腺癌的进展。

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.