ONC201 kills breast cancer cells in vitro by targeting mitochondria
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Yoshimi Endo Greer1, Natalie Porat-Shliom2, Kunio Nagashima3, Christina Stuelten2, Dan Crooks4, Vishal N. Koparde5, Samuel F. Gilbert1, Celia Islam1, Ashley Ubaldini1, Yun Ji6, Luca Gattinoni6, Ferri Soheilian3, Xiantao Wang7, Markus Hafner7, Jyoti Shetty8, Bao Tran8, Parthav Jailwala5, Maggie Cam5, Martin Lang4, Donna Voeller1, William C. Reinhold9, Vinodh Rajapakse9, Yves Pommier9, Roberto Weigert2, W. Marston Linehan4 and Stanley Lipkowitz1
1Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
2Laboratory of Cellular and Molecular Biology, CCR, NCI, NIH, Bethesda, MD, USA
3Electron Microscope Laboratory, Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research (FNLCR), Frederick, MD, USA
4Urologic Oncology Branch, CCR, NCI, NIH, Bethesda, MD, USA
5CCR Collaborative Bioinformatics Resource, Leidos Biomedical Research, Inc., FNLCR, Frederick, MD, USA
6Experimental Transplantation and Immunology Branch, CCR, NCI, NIH, Bethesda, MD, USA
7RNA Molecular Biology Group, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA
8CCR Sequencing Facility, Leidos Biomedical Research, Inc., FNLCR, Frederick, MD, USA
9Developmental Therapeutics Branch, CCR, NCI, NIH, Bethesda, MD, USA
Stanley Lipkowitz, email: [email protected]
Keywords: ONC201; breast cancer; mitochondria
Received: November 03, 2017 Accepted: March 06, 2018 Published: April 06, 2018
We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201.
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