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: 8937805
• 负责人: Leonard Neckers
• 金额: $ 33.4万
• 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/8937805
• 关键词: Animals; Binding; Biological Factors; Cardiac; Cardiotoxicity; Cell Line; Cells; Congestive Heart Failure; Consumption; 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 Crista; Mitochondrial DNA; Molecular; Mus; Myocardium; Patients; Phenotype; Phosphorylation; Predisposing Factor; Predisposition; Production; Protein Kinase C; Proteins; Pyruvate; Renal carcinoma; Respiratory Chain; Role; Single Nucleotide Polymorphism; Specimen; Testing; Time; Tissues; Topoisomerase; Type I DNA Topoisomerases; Vertebrates; Wild Type Mouse; addiction; base; cancer type; chemotherapeutic agent; heat-shock factor 1; insulin signaling; mitochondrial dysfunction; neoplastic cell; novel; novel therapeutic intervention; response; transcription factor; 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，同时激活HSF1，在肾癌中引起药理学诱导的合成致死。Englerin A （EA）结合并激活蛋白激酶C-theta （PKCtheta）。ea依赖性激活PKCtheta诱导胰岛素抵抗表型，限制肿瘤细胞进入葡萄糖。同时，EA引起pkctheta介导的磷酸化和转录因子热休克因子1的激活，这是葡萄糖依赖的诱导剂。通过促进葡萄糖成瘾，同时使细胞缺乏葡萄糖，EA被证明对高度糖酵解的肿瘤（包括肾癌）具有合成致死性。我们还合作进行了一项研究，表明线粒体拓扑异构酶I （Top1mt）是阿霉素心脏毒性的一个新的限制因素。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，易致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病变和线粒体功能障碍，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）小鼠可能对小鼠遗传失活的Top1mt表现出过敏，从而加剧了DOX治疗后心脏组织中mtDNA拷贝数的丢失和mtDNA损伤。Top1mt敲除小鼠也不能维持呼吸链蛋白的产生和线粒体嵴超微结构的组织。在DOX处理的动物中，这些线粒体缺陷导致氧气消耗减少、ROS产生增加和心肌损伤加剧。因此，Top1mt基因敲除小鼠在最后一次注射DOX后45天内死亡，而野生型小鼠存活。我们的研究结果证明，线粒体拓扑异构酶I （Top1mt）在脊椎动物中是保守的，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）检测在研究患者对DOX诱导的心脏毒性的易感性方面的潜力。