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ONC201 kills breast cancer cells in vitro by targeting mitochondria

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....

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Autores principales: Greer, Yoshimi Endo, Porat-Shliom, Natalie, Nagashima, Kunio, Stuelten, Christina, Crooks, Dan, Koparde, Vishal N., Gilbert, Samuel F., Islam, Celia, Ubaldini, Ashley, Ji, Yun, Gattinoni, Luca, Soheilian, Ferri, Wang, Xiantao, Hafner, Markus, Shetty, Jyoti, Tran, Bao, Jailwala, Parthav, Cam, Maggie, Lang, Martin, Voeller, Donna, Reinhold, William C., Rajapakse, Vinodh, Pommier, Yves, Weigert, Roberto, Linehan, W. Marston, Lipkowitz, Stanley
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915085/
https://www.ncbi.nlm.nih.gov/pubmed/29719618
http://dx.doi.org/10.18632/oncotarget.24862
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author Greer, Yoshimi Endo
Porat-Shliom, Natalie
Nagashima, Kunio
Stuelten, Christina
Crooks, Dan
Koparde, Vishal N.
Gilbert, Samuel F.
Islam, Celia
Ubaldini, Ashley
Ji, Yun
Gattinoni, Luca
Soheilian, Ferri
Wang, Xiantao
Hafner, Markus
Shetty, Jyoti
Tran, Bao
Jailwala, Parthav
Cam, Maggie
Lang, Martin
Voeller, Donna
Reinhold, William C.
Rajapakse, Vinodh
Pommier, Yves
Weigert, Roberto
Linehan, W. Marston
Lipkowitz, Stanley
author_facet Greer, Yoshimi Endo
Porat-Shliom, Natalie
Nagashima, Kunio
Stuelten, Christina
Crooks, Dan
Koparde, Vishal N.
Gilbert, Samuel F.
Islam, Celia
Ubaldini, Ashley
Ji, Yun
Gattinoni, Luca
Soheilian, Ferri
Wang, Xiantao
Hafner, Markus
Shetty, Jyoti
Tran, Bao
Jailwala, Parthav
Cam, Maggie
Lang, Martin
Voeller, Donna
Reinhold, William C.
Rajapakse, Vinodh
Pommier, Yves
Weigert, Roberto
Linehan, W. Marston
Lipkowitz, Stanley
author_sort Greer, Yoshimi Endo
collection PubMed
description 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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spelling pubmed-59150852018-05-01 ONC201 kills breast cancer cells in vitro by targeting mitochondria Greer, Yoshimi Endo Porat-Shliom, Natalie Nagashima, Kunio Stuelten, Christina Crooks, Dan Koparde, Vishal N. Gilbert, Samuel F. Islam, Celia Ubaldini, Ashley Ji, Yun Gattinoni, Luca Soheilian, Ferri Wang, Xiantao Hafner, Markus Shetty, Jyoti Tran, Bao Jailwala, Parthav Cam, Maggie Lang, Martin Voeller, Donna Reinhold, William C. Rajapakse, Vinodh Pommier, Yves Weigert, Roberto Linehan, W. Marston Lipkowitz, Stanley Oncotarget Research Paper 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. Impact Journals LLC 2018-04-06 /pmc/articles/PMC5915085/ /pubmed/29719618 http://dx.doi.org/10.18632/oncotarget.24862 Text en Copyright: © 2018 Greer et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Greer, Yoshimi Endo
Porat-Shliom, Natalie
Nagashima, Kunio
Stuelten, Christina
Crooks, Dan
Koparde, Vishal N.
Gilbert, Samuel F.
Islam, Celia
Ubaldini, Ashley
Ji, Yun
Gattinoni, Luca
Soheilian, Ferri
Wang, Xiantao
Hafner, Markus
Shetty, Jyoti
Tran, Bao
Jailwala, Parthav
Cam, Maggie
Lang, Martin
Voeller, Donna
Reinhold, William C.
Rajapakse, Vinodh
Pommier, Yves
Weigert, Roberto
Linehan, W. Marston
Lipkowitz, Stanley
ONC201 kills breast cancer cells in vitro by targeting mitochondria
title ONC201 kills breast cancer cells in vitro by targeting mitochondria
title_full ONC201 kills breast cancer cells in vitro by targeting mitochondria
title_fullStr ONC201 kills breast cancer cells in vitro by targeting mitochondria
title_full_unstemmed ONC201 kills breast cancer cells in vitro by targeting mitochondria
title_short ONC201 kills breast cancer cells in vitro by targeting mitochondria
title_sort onc201 kills breast cancer cells in vitro by targeting mitochondria
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915085/
https://www.ncbi.nlm.nih.gov/pubmed/29719618
http://dx.doi.org/10.18632/oncotarget.24862
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