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Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A

Keighley N. Reisenauer, Yongfeng Tao, Shuxuan Song, Saawan D. Patel, Alec Ingros, Peter Sheesley, Marco Masi, Angela Boari, Antonio Evidente, Alexander V. Kornienko, Daniel Romo, Joseph Taube
doi: https://doi.org/10.1101/2020.05.06.079343
Keighley N. Reisenauer
1Department of Biology, Baylor University, Waco, TX, USA
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Yongfeng Tao
2Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA
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Shuxuan Song
1Department of Biology, Baylor University, Waco, TX, USA
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Saawan D. Patel
1Department of Biology, Baylor University, Waco, TX, USA
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Alec Ingros
1Department of Biology, Baylor University, Waco, TX, USA
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Peter Sheesley
1Department of Biology, Baylor University, Waco, TX, USA
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Marco Masi
3Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario Monte Sant’Angelo, Naples, Italy
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Angela Boari
4Institute of Sciences and Food Production, CNR, Bari, Italy
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Antonio Evidente
3Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario Monte Sant’Angelo, Naples, Italy
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Alexander V. Kornienko
5Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, USA
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Daniel Romo
2Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA
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Joseph Taube
1Department of Biology, Baylor University, Waco, TX, USA
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  • For correspondence: Joseph_Taube@baylor.edu
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Abstract

The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapy, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover, prolonged, sub-cytotoxic exposure to OpA is sufficient to reduce migration, sphere formation, and resistance to doxorubicin. OpA is well-tolerated in mice and treatment with OpA alone reduces tumor burden. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 08, 2020.
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Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A
Keighley N. Reisenauer, Yongfeng Tao, Shuxuan Song, Saawan D. Patel, Alec Ingros, Peter Sheesley, Marco Masi, Angela Boari, Antonio Evidente, Alexander V. Kornienko, Daniel Romo, Joseph Taube
bioRxiv 2020.05.06.079343; doi: https://doi.org/10.1101/2020.05.06.079343
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Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A
Keighley N. Reisenauer, Yongfeng Tao, Shuxuan Song, Saawan D. Patel, Alec Ingros, Peter Sheesley, Marco Masi, Angela Boari, Antonio Evidente, Alexander V. Kornienko, Daniel Romo, Joseph Taube
bioRxiv 2020.05.06.079343; doi: https://doi.org/10.1101/2020.05.06.079343

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