RT Journal Article
SR Electronic
T1 Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.06.079343
DO 10.1101/2020.05.06.079343
A1 Keighley N. Reisenauer
A1 Yongfeng Tao
A1 Shuxuan Song
A1 Saawan D. Patel
A1 Alec Ingros
A1 Peter Sheesley
A1 Marco Masi
A1 Angela Boari
A1 Antonio Evidente
A1 Alexander V. Kornienko
A1 Daniel Romo
A1 Joseph Taube
YR 2020
UL http://biorxiv.org/content/early/2020/05/08/2020.05.06.079343.abstract
AB 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 StatementThe authors have declared no competing interest.