Role of HSP90 and its co-chaperone FKBP51 in the pathogenesis of Cushing's syndrome

HSP90 及其共伴侣 FKBP51 在库欣综合征发病机制中的作用

• 批准号: 286003474
• 负责人: Professor Dr. Felix Beuschlein
• 金额: --
• 依托单位: Max-Planck-Institut für Psychiatrie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/286003474?language=en
• 关键词: Role; HSP90; its; co; chaperone

Clinical signs and symptoms of Cushing syndrome are caused by endogenous hypercortisolism due to an ACTH secreting pituitary or ectopic source or autonomous production of cortisol by the adrenal gland. Unsuccessfully treated Cushing syndrome has a high burden of morbidity and mortality. The molecular chaperone Hsp90 (heat shock protein 90) folds and stabilizes many kinases and transcription factors that have oncogenic properties and are required for tumor growth. The alpha isoform of Hsp90 is over-expressed in many types of solid tumors thereby constituting a validated target for cancer therapy. In fact, currently, several Hsp90 inhibitors are being tested in clinical trials. Hsp90 is also essential for the proper folding and stabilization of the glucocorticoid receptor (GR). The interaction between Hsp90 and GR is strongly affected by the co-chaperone FKBP51 that acts as a binding partner, forming a functional complex. Furthermore, overexpression of Hsp90 has a negative influence on the transcriptional activity of GR. This inhibitory effect of Hsp90 on GR resembles the partial glucocorticoid resistance observed in ACTH-secreting adenomas of the pituitary and of tumors causing ectopic Cushing syndrome. We could recently show that C-terminal Hsp90 inhibitors can restore the sensitivity to glucocorticoids in models of Cushing disease and thereby normalize ACTH levels. Furthermore, there is good evidence that GR within the adrenal is tightly regulated by ACTH thereby forming a positive ultra-short regulatory loop exerted by GR supporting a complex intra-adrenal GR-mediated feedback. Within the proposed working program, we aim at in depth characterization of the complex interplay of Hsp90 dependent mechanisms within the pituitary-adrenal-axis. Specifically, the first aim of our project is to quantify Hsp90-alpha and FKBP51 expression in a large cohort of biopsies from pituitary and adrenal tumors from patients with Cushing syndrome in order to correlate them with clinical parameters including hormonal parameters, tumor characteristics and cardiovascular and metabolic endpoints. Our second aim is to characterize the biochemical interactions between Hsp90, FKBP51, and GR, as well as SREBP1 and CREB that control the production of ACTH and cortisol in corticotroph and adrenocortical cells. We will further investigate the impact of these mechanisms on oncoproteins and cell proliferation. In parallel, we will examine the in vivo effects of FKBP51 and Hsp90 inhibitors on mouse models with the prospect of using these results to design more potent and selective compounds for the treatment of Cushing syndrome and potentially other endocrine malignancies. Together, the results we expect from this project will constitute a full characterization of the mechanism of action of Hsp90 inhibitors on ACTH- and cortisol-secreting tumors.

库欣综合征的临床体征和症状是由内源性皮质醇增多症引起的，内源性皮质醇增多症是由于垂体分泌ACTH或异位来源或肾上腺自主产生皮质醇所致。治疗不成功的库欣综合征具有较高的发病率和死亡率。分子伴侣Hsp 90（热休克蛋白90）折叠和稳定许多激酶和转录因子，这些激酶和转录因子具有致癌特性，是肿瘤生长所必需的。Hsp 90的α同种型在许多类型的实体瘤中过表达，从而构成癌症治疗的经验证的靶标。事实上，目前，几种Hsp 90抑制剂正在临床试验中进行测试。Hsp 90对于糖皮质激素受体（GR）的正确折叠和稳定也至关重要。Hsp 90和GR之间的相互作用受到作为结合伴侣的辅伴侣FKBP 51的强烈影响，形成功能复合物。此外，Hsp 90的过度表达对GR的转录活性具有负面影响。Hsp 90对GR的这种抑制作用类似于在垂体ACTH分泌腺瘤和引起异位库欣综合征的肿瘤中观察到的部分糖皮质激素抵抗。我们最近发现C-末端Hsp 90抑制剂可以恢复库欣病模型对糖皮质激素的敏感性，从而使ACTH水平正常化。此外，有充分的证据表明，肾上腺内的GR受到ACTH的严格调节，从而形成由GR施加的正性超短调节环，支持复杂的肾上腺内GR介导的反馈。在拟议的工作计划中，我们的目标是深入表征垂体-肾上腺轴内的Hsp 90依赖机制的复杂相互作用。具体而言，我们项目的第一个目的是量化库欣综合征患者垂体和肾上腺肿瘤活检组织中Hsp 90-α和FKBP 51的表达，以将其与临床参数（包括激素参数、肿瘤特征以及心血管和代谢终点）相关联。我们的第二个目的是表征Hsp 90，FKBP 51和GR之间的生化相互作用，以及SREBP 1和CREB控制促肾上腺皮质激素细胞和肾上腺皮质细胞中ACTH和皮质醇的产生。我们将进一步研究这些机制对癌蛋白和细胞增殖的影响。同时，我们将研究FKBP 51和Hsp 90抑制剂对小鼠模型的体内作用，并利用这些结果设计更有效和选择性的化合物用于治疗库欣综合征和潜在的其他内分泌恶性肿瘤的前景。总之，我们期望从这个项目中得到的结果将构成Hsp 90抑制剂对ACTH和皮质醇分泌肿瘤作用机制的完整表征。

项目成果

Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter

抑制热休克因子 1 增强 POMC 启动子的抑制分子机制

• DOI: 10.1159/000500200
• 发表时间: 2019
• 期刊: Neuroendocrinology
• 影响因子: 4.1
• 作者: Ciato D;Monteserin Garcia JL;Papst L;D'Annunzio S;Hristov M;Tichomirowa MA;Belaya Z;Rozhinskaya L;Buchfelder M;Theodoropoulou M;Paez‐Pereda M;Stalla GK
• 通讯作者: Stalla GK