Title |
ONC201 kills breast cancer cells in vitro by targeting mitochondria
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Published in |
Oncotarget, April 2018
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DOI | 10.18632/oncotarget.24862 |
Pubmed ID | |
Authors |
Yoshimi Endo Greer, Natalie Porat-Shliom, Kunio Nagashima, Christina Stuelten, Dan Crooks, Vishal N. Koparde, Samuel F. Gilbert, Celia Islam, Ashley Ubaldini, Yun Ji, Luca Gattinoni, Ferri Soheilian, Xiantao Wang, Markus Hafner, Jyoti Shetty, Bao Tran, Parthav Jailwala, Maggie Cam, Martin Lang, Donna Voeller, William C. Reinhold, Vinodh Rajapakse, Yves Pommier, Roberto Weigert, W. Marston Linehan, Stanley Lipkowitz |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | 38% |
Australia | 1 | 13% |
Brazil | 1 | 13% |
Unknown | 3 | 38% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 7 | 88% |
Science communicators (journalists, bloggers, editors) | 1 | 13% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 66 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 13 | 20% |
Researcher | 12 | 18% |
Student > Bachelor | 7 | 11% |
Other | 4 | 6% |
Student > Postgraduate | 4 | 6% |
Other | 8 | 12% |
Unknown | 18 | 27% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 14 | 21% |
Medicine and Dentistry | 8 | 12% |
Pharmacology, Toxicology and Pharmaceutical Science | 7 | 11% |
Agricultural and Biological Sciences | 6 | 9% |
Business, Management and Accounting | 2 | 3% |
Other | 7 | 11% |
Unknown | 22 | 33% |