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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010683-11
Application #
9153634
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Rai, Ganesha; Brimacombe, Kyle R; Mott, Bryan T et al. (2017) Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH). J Med Chem 60:9184-9204
Sourbier, Carole; Neckers, Len (2017) Uncoupling tumor-stroma interactions in breast cancer patients. Semin Oncol 44:235-236
Sourbier, Carole; Scroggins, Bradley T; Mannes, Philip Z et al. (2015) Tonantzitlolone cytotoxicity toward renal cancer cells is PKC?- and HSF1-dependent. Oncotarget 6:29963-74
Khiati, Salim; Baechler, Simone A; Factor, Valentina M et al. (2015) Lack of mitochondrial topoisomerase I (TOP1mt) impairs liver regeneration. Proc Natl Acad Sci U S A 112:11282-7
Moses, Michael A; Neckers, Len (2015) The GLU that holds cancer together: targeting GLUtamine transporters in breast cancer. Cancer Cell 27:317-9
Sourbier, Carole; Ricketts, Christopher J; Matsumoto, Shingo et al. (2014) Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell 26:840-850
Khiati, Salim; Dalla Rosa, Ilaria; Sourbier, Carole et al. (2014) Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin Cancer Res 20:4873-81
Sourbier, Carole; Scroggins, Bradley T; Ratnayake, Ranjala et al. (2013) Englerin A stimulates PKC? to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality. Cancer Cell 23:228-37
Neckers, Len; Ricketts, Christopher J; Marston Linehan, W (2013) New Insights into von Hippel-Lindau Function Highlighted by Investigation of the Trichloroethylene-Induced p.P81S Hotspot Mutation. J Natl Cancer Inst 105:1339-40
Douarre, Celine; Sourbier, Carole; Dalla Rosa, Ilaria et al. (2012) Mitochondrial topoisomerase I is critical for mitochondrial integrity and cellular energy metabolism. PLoS One 7:e41094

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