Role of FH loss in development of HLRCC heriditary kidney cancer

2014年，我们发现天然产物englerin A刺激PKCtheta抑制胰岛素信号转导，同时激活HSF1，导致药物诱导的肾癌合成致死。Engerin A(EA)与蛋白激酶C-theta(PKCtheta)结合并激活。依赖EA激活的PKCtheta诱导胰岛素抵抗表型，限制肿瘤细胞对葡萄糖的访问。同时，电针引起PKCtheta介导的磷酸化和转录因子热休克因子1的激活，热休克因子1是葡萄糖依赖的诱导者。通过促进葡萄糖成瘾，同时使细胞葡萄糖饥饿，EA被证明对包括肾癌在内的高度糖酵解肿瘤具有综合致命性。我们还合作了一项研究，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子。阿霉素(DOX)是目前最有效的化疗药物之一。然而，接受DOX治疗的患者中，多达30%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。根据已发现暴露于DOX的人心脏线粒体DNA损伤和线粒体功能障碍，以及线粒体拓扑异构酶1(Top1mt)特异性地控制mtDNA动态平衡，我们假设Top1mt基因敲除(KO)小鼠可能对Top1mt基因失活表现出超敏反应，加剧了DOX治疗后心脏组织中mtDNA拷贝数的丢失和mtDNA损伤。Top1mt基因敲除小鼠也不能维持呼吸链蛋白的产生和线粒体脊超微结构的组织。这些线粒体缺陷导致DOX治疗的动物氧气消耗减少，ROS产生增加，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。我们的结果提供了证据，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的耐受和对DOX心脏毒性的适应性反应是至关重要的。他们还提出了Top1mt单核苷酸多态(SNP)测试在调查患者对DOX引起的心脏毒性的易感性方面的潜力。

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.