Role of FH loss in development of HLRCC heriditary kidney cancer

FH 缺失在 HLRCC 遗传性肾癌发展中的作用

• 批准号: 9556337
• 负责人: Leonard Neckers
• 金额: $ 45.65万
• 依托单位: DIVISION OF BASIC 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/9556337
• 关键词: Animals; Binding; Cardiac; Cardiotoxicity; Cell Line; Cells; Congestive Heart Failure; Consumption; Crista ampullaris; Defect; Dependence; Development; Doxorubicin; Exhibits; Fumarate Hydratase; Genetic; Glucose; HSF1; Heart; Hereditary Leiomyomatosis and Renal Cell Cancer; Homeostasis; Human; Hypersensitivity; Injection of therapeutic agent; Insulin Resistance; Knockout Mice; Knowledge; Lesion; Malignant Neoplasms; Mediating; Mitochondria; Mitochondrial DNA; Molecular; Mus; Myocardium; Natural Products; Patients; Pharmacology; Phenotype; Phosphorylation; Predisposing Factor; Predisposition; Production; Protein Kinase C; Proteins; Pyruvate; Renal carcinoma; Respiratory Chain; Role; Single Nucleotide Polymorphism; Specimen; Testing; Time; Tissues; Topoisomerase; Transcriptional Activation; Type I DNA Topoisomerases; Vertebrates; Wild Type Mouse; addiction; base; cancer type; chemotherapeutic agent; heat shock transcription factor; insulin signaling; mitochondrial dysfunction; neoplastic cell; novel; novel therapeutic intervention; protein activation; response; treatment strategy; tumor

In 2014, we showed that the natural product englerin A stimulates PKCtheta to inhibit insulin signaling and to simultaneously activate HSF1, causing pharmacologically induced synthetic lethality in renal cancer. Englerin A (EA) binds to and activates protein kinase C-theta (PKCtheta). EA-dependent activation of PKCtheta induces an insulin-resistant phenotype, limiting the access of tumor cells to glucose. At the same time, EA causes PKCtheta-mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. By promoting glucose addiction, while simultaneously starving cells of glucose, EA proves to be synthetically lethal to highly glycolytic tumors, including renal cancer. We also collaborated on a study showing that Mitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, up to 30% of the patients treated with DOX suffer from congestive heart failure. The mechanism of DOX cardiotoxicity is likely multifactorial and most importantly, the genetic factors predisposing to DOX cardiotoxicity are unknown. Based on the fact that mtDNA lesions and mitochondrial dysfunctions have been found in human hearts exposed to DOX and that mitochondrial topoisomerase 1 (Top1mt) specifically controls mtDNA homeostasis, we hypothesized that Top1mt knockout (KO) mice might exhibit hypersensitivity to Genetic inactivation of Top1mt in mice accentuates mtDNA copy number loss and mtDNA damage in heart tissue following DOX treatment. Top1mt knockout mice also fail to maintain respiratory chain protein production and mitochondrial cristae ultrastructure organization. These mitochondrial defects result in decreased O2 consumption, increased ROS production and enhanced heart muscle damage in animals treated with DOX. Accordingly, Top1mt knockout mice die within 45 days after the last DOX injection under conditions whereas the wild type mice survive. Our results provide evidence that mitochondrial topoisomerase I, Top1mt, which is conserved across vertebrates, is critical for cardiac tolerance to DOX and adaptive response to DOX cardiotoxicity. They also suggest the potential of Top1mt single nucleotide polymorphisms (SNP) testing to investigate patient susceptibility to DOX induced cardiotoxicity.

2014 年，我们发现天然产物 englerin A 刺激 PKCtheta 抑制胰岛素信号传导，同时激活 HSF1，从而在肾癌中引起药理诱导的合成致死作用。 Englerin A (EA) 结合并激活蛋白激酶 C-theta (PKCtheta)。 PKCtheta 的 EA 依赖性激活会诱导胰岛素抵抗表型，从而限制肿瘤细胞获取葡萄糖。同时，EA 引起 PKCtheta 介导的磷酸化和转录因子热休克因子 1（葡萄糖依赖性诱导剂）的激活。通过促进葡萄糖成瘾，同时使细胞饥饿，EA 被证明对高度糖酵解肿瘤（包括肾癌）具有综合致命性。我们还合作开展了一项研究，表明线粒体拓扑异构酶 I (Top1mt) 是阿霉素心脏毒性的新型限制因素。阿霉素（DOX）是最有效的化疗药物之一。然而，高达 30% 的接受 DOX 治疗的患者患有充血性心力衰竭。 DOX 心脏毒性的机制可能是多因素的，最重要的是，导致 DOX 心脏毒性的遗传因素尚不清楚。基于在暴露于 DOX 的人类心脏中发现 mtDNA 损伤和线粒体功能障碍以及线粒体拓扑异构酶 1 (Top1mt) 特异性控制 mtDNA 稳态的事实，我们假设 Top1mt 敲除 (KO) 小鼠可能表现出对小鼠 Top1mt 遗传失活加剧 mtDNA 的超敏反应 DOX 治疗后心脏组织中的拷贝数丢失和线粒体 DNA 损伤。 Top1mt 敲除小鼠也无法维持呼吸链蛋白的产生和线粒体嵴超微结构组织。这些线粒体缺陷导致接受 DOX 治疗的动物的 O2 消耗减少、ROS 产生增加和心肌损伤加剧。因此，Top1mt 敲除小鼠在最后一次 DOX 注射后 45 天内死亡，而野生型小鼠则存活。我们的结果提供证据表明，在脊椎动物中保守的线粒体拓扑异构酶 I Top1mt 对于心脏对 DOX 的耐受性和对 DOX 心脏毒性的适应性反应至关重要。他们还提出了 Top1mt 单核苷酸多态性 (SNP) 测试在研究患者对 DOX 引起的心脏毒性的易感性方面的潜力。