HSP90 and HSP7Chaperone Proteins and Interactors in Cellular Signal Transduction

细胞信号转导中的 HSP90 和 HSP7 伴侣蛋白和相互作用物

• 批准号: 10926578
• 负责人: Leonard Neckers
• 金额: $ 89.78万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926578
• 关键词: Address; Alternative Splicing; Androgen Receptor; Androgens; Ants; Area; Binding; Carbon; Castration; Cells; Citric Acid Cycle; Client; Complex; Dependence; Development; Electron Transport; Genetic Transcription; Glutamine; HSF1; Heat-Shock Proteins 90; Homologous Gene; In Vitro; Knock-out; Length; Ligand Binding Domain; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Metabolic; Mitochondria; Mitochondrial Proteins; Molecular Chaperones; Neoplasm Metastasis; Outcome; Oxidative Phosphorylation; Phenocopy; Phosphotransferases; Production; Prostate; Proteins; Pyruvate; RNA Splicing; Regulation; Renal carcinoma; Reproducibility; Research; Residual state; Resistance; Respiration; Role; Signal Transduction; Source; Translations; Urologic Diseases; cancer site; castration resistant prostate cancer; drug development; enzalutamide; in vivo; inhibitor; magnetic resonance spectroscopic imaging; monomer; non-invasive imaging; novel; novel strategies; preference

We confirmed that alternatively spliced androgen receptor (lacking ligand binding domain with which Hsp90 interacts) interacts with and remains dependent on Hsp40 and Hsp70 for stability and transcriptional activity. Further, we showed that targeting the Hsp40/Hsp70 chaperone axis is a novel strategy to treat castration-resistant prostate cancer that has become resistant to standard ant-iandrogen therapy. (2) We identified a multichaperone complex in mitochondria comprised of Trap1, Hsp60 and mitochondrial Hsp70 as a regulator of oxidative phosphorylation and ATP synthase-mediated ATP production. Assembly of the multichaperone complex is sensitive to mitochondrial ATP level. We identified multiple subunits of ATP synthase and numerous electron transport chain components as Trap1 interactors (potential clients), and we demonstrated that Trap1 knockout leads to increased oxidative phosphorylation and a strong preference for glutamine as the primary carbon source for the TCA cycle. (3) We also demonstrated that Hsp70 inhibition blocked both heat-induced and Hsp90 inhibitor-potentiated HSF1 activation and transcriptional activity by causing the destabilization of HSF1. We showed that Hsp70 bound to both HSF1 monomers (inactive) and trimers (active). confirmed in vitro and in vivo activity of Hsp70 inhibitor on castrate resistant prostate, but demonstrated an early and profound effect on mitochondrial protein translation which leads to disruption of electron transport chain (ETC) complex I, with resultant collapse of the ETC. This outcome is phenocopied by a specific inhibitor of complex I. In both cases, disruption of mitochondrial respiration restores sensitivity to enzalutamide as long as residual wild type androgen is present. In vitro effects are reproducible in vivo and can be non-invasively imaged with hyperpolarized pyruvate MR spectroscopy (HP-MRSI).

我们证实，选择性剪接雄激素受体（缺乏与Hsp90相互作用的配体结合结构域）与Hsp40和Hsp70相互作用，并保持依赖于Hsp40和Hsp70的稳定性和转录活性。此外，我们表明，靶向Hsp40/Hsp70伴侣轴是治疗对标准抗雄激素疗法具有抗性的去势抵抗性前列腺癌的新策略。(2)我们确定了一个多分子伴侣复合物组成的Trap1，热休克蛋白60和线粒体热休克蛋白70作为氧化磷酸化和ATP酶介导的ATP生产的调节剂。多伴侣复合物的组装对线粒体ATP水平敏感。我们确定了ATP合酶的多个亚基和许多电子传递链组件作为Trap1相互作用物（潜在客户），我们证明了Trap1敲除导致氧化磷酸化增加和对谷氨酰胺作为TCA循环的主要碳源的强烈偏好。(3)我们还表明，热休克蛋白70抑制阻断热诱导和热休克蛋白90的增强HSF1的激活和转录活性引起的不稳定的HSF1。我们发现，Hsp70结合HSF1单体（无活性）和三聚体（活性）。证实了Hsp70抑制剂对去势抵抗性前列腺的体外和体内活性，但证明了对线粒体蛋白翻译的早期和深远的影响，这导致电子传递链（ETC）复合物I的破坏，从而导致ETC的崩溃。在这两种情况下，只要存在残留的野生型雄激素，线粒体呼吸破坏就会恢复对Enzalutamide的敏感性。体外效应在体内是可重现的，并且可以用超极化丙酮酸盐MR光谱（HP-MRSI）进行非侵入性成像。

项目成果

The therapeutic target Hsp90 and cancer hallmarks.

治疗靶标 Hsp90 和癌症标志。

• DOI: 10.2174/138161213804143725
• 发表时间: 2013
• 期刊: Current pharmaceutical design
• 影响因子: 3.1
• 作者: Miyata Y;Nakamoto H;Neckers L
• 通讯作者: Neckers L

Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants.

• DOI: 10.1371/journal.pone.0141786
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Prince TL;Kijima T;Tatokoro M;Lee S;Tsutsumi S;Yim K;Rivas C;Alarcon S;Schwartz H;Khamit-Kush K;Scroggins BT;Beebe K;Trepel JB;Neckers L
• 通讯作者: Neckers L

Inhibition of cancer invasion and metastasis by targeting the molecular chaperone heat-shock protein 90.

• 发表时间: 2009-03
• 期刊: Anticancer research
• 影响因子: 2
• 作者: F. Koga;K. Kihara;L. Neckers

Contributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity.

• DOI: 10.4155/fmc.13.88
• 发表时间: 2013-06
• 期刊: Future medicinal chemistry
• 影响因子: 4.2
• 作者: Walton-Diaz A;Khan S;Bourboulia D;Trepel JB;Neckers L;Mollapour M
• 通讯作者: Mollapour M

Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

• DOI: 10.1016/j.chembiol.2013.08.004
• 发表时间: 2013-09-19
• 期刊: Chemistry & biology
• 作者: Barrott JJ;Hughes PF;Osada T;Yang XY;Hartman ZC;Loiselle DR;Spector NL;Neckers L;Rajaram N;Hu F;Ramanujam N;Vaidyanathan G;Zalutsky MR;Lyerly HK;Haystead TA
• 通讯作者: Haystead TA