PROSTATIC DIFFERENTIATION AND SEX HORMONE METABOLISM

前列腺分化和性激素代谢

• 批准号: 2683398
• 负责人: Shuk-Mei Ho
• 金额: $ 22.1万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-30 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683398
• 关键词: JAK kinase; autocrine; bromocriptine; epidermal growth factor; estradiol; estrogen receptors; growth factor receptors; hormone inhibitor; hormone regulation /control mechanism; hormone related neoplasm /cancer; hyperprolactinemia; laboratory rat; phosphorylation; prolactin; prostate preneoplastic state; quercetin; receptor expression; steroid hormone metabolism; testosterone; transforming growth factors

We previously demonstrated that simultaneous treatment of intact Noble (NBL) rats with testosterone (T) and estradiol-17 beta (e2) for 16 weeks consistently induced dysplasia exclusively. In the dorsolateral prostate (DLP) of all treated animals. This hormone- induced lesion in rat DLP closely resembles human prostatic intraepithelial neoplasia and likely gives rise to carcinomas which develop in all animals treated with this hormonal regimen for life- time. Our recent findings indicate that the T+E2 action in rat DLP involves two independent or interdependent early events: a) elevation of a moderate affinity, high capacity estrogen binding site (type II EBS) in the DLP and b) hyperprolactinemia. Inhibition of either one of the two events by specific inhibitors blocks dysplasia development, thus suggesting that they both are important contributors to the genesis the DLP lesion. We now hypothesize that 10 elevation of type II EBS leads to upregulation of transformation growth factor alpha (TGF alpha) and its cognate receptor, epidermal growth factor receptor (EGFr) in rat DLP, and 2) hyperprolactinemia augments PRL receptor (PRLr) expression and activates PRLr signaling pathways in this prostatic lobe. Conjointly, these two cascades of events would induce incessant cell proliferation and thereby eventually neoplastic transformation in this tissue. Using quercetin (Q), which we found to be an inhibitor of DLP type II EBS, and bromocriptine (Br), an inhibitor of PRL release from the pituitary, we shall seek evidence in whole animal studies that these two cascades mediate T=E2 action and enhancement of epithelial cell proliferation in the DLP. Additionally, to a DLP organ culture system, T+2,, with and without Q, will be added to culture medium to ascertain whether T+E2 directly induces type II EBS elevation and if Q inhibits the sex hormone-action. Direct involvement of the TGF alpha/EGFR autocrine loop in epithelial cell proliferation will be tested in vitro by supplementation of DLP culture medium with the ligand or an anti-EGFr antiserum. Lastly, DLP cultures will be challenged with PRL to determine if activation of the PRLR is attended by physical association, upregulation, and/or phosphorylation of the Janus kinase-2 (JAK-2) and Raf-1, the purported activating signaling molecules of PRLR action.

我们以前证明，同时治疗完整的 用睾酮（T）和雌二醇-17 β（e2）治疗的Noble（NBL）大鼠， 16周持续诱导发育不良。在 背外侧前列腺（DLP）。 这种荷尔蒙- 大鼠DLP的诱导损伤与人前列腺非常相似 上皮内瘤形成，并可能引起癌， 在所有接受这种激素治疗的动物身上发展- 时间 我们最近的研究结果表明，T+E2在大鼠DLP中的作用 涉及两个独立或相互依赖的早期事件：a）升高 中等亲和力、高容量雌激素结合位点（II型 EBS）和B）高泌乳素血症。 抑制任何一种 特异性抑制剂阻断发育异常 发展，这表明它们都很重要。 导致DLP病变的原因。 我们现在假设 II型EBS的升高导致转化的上调 生长因子α（TGF α）及其同源受体，表皮 生长因子受体（EGFr）在大鼠DLP，和2）高泌乳素血症 增强PRL受体（PRLr）表达并激活PRLr 前列腺叶中的信号通路 结合起来，这两个 一连串的事件会诱导细胞不断增殖， 从而最终在该组织中发生肿瘤转化。 使用 槲皮素（Q），我们发现它是DLP II型的抑制剂 EBS和溴隐亭（Br），一种PRL释放抑制剂， 垂体，我们将在整个动物研究中寻找证据， 两个级联介导T=E2作用和上皮细胞增殖的增强。 DLP中的细胞增殖。 此外，DLP器官培养 将含和不含Q的T+2系统加入培养基中 确定T+E2是否直接诱导II型EBS升高 Q是否抑制了性行为。 直接参与 TGF α/EGFR自分泌环在上皮细胞增殖中的作用 通过补充DLP培养基进行体外测试， 配体或抗EGFr抗血清。 最后，DLP文化将 用PRL激发以确定PRLR的激活是否 参与物理关联，上调，和/或 Janus激酶-2（JAK-2）和Raf-1的磷酸化， 据称激活PRLR作用的信号分子。