Role of FH loss in development of HLRCC heriditary kidney cancer

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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.