Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate
Abstract Triple-negative breast cancer (TNBC) is a difficult-to-treat, aggressive cancer type. TNBC is often associated with the cellular program of epithelial-mesenchymal transition (EMT) that confers drug resistance and metastasis. EMT and reverse mesenchymal-epithelial transition (MET) programs a...
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| Format: | Article |
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Nature Portfolio
2024-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-50710-3 |
| _version_ | 1827388490007969792 |
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| author | Mirko Terragno Anastassiya Vetrova Oleg Semenov A. Emre Sayan Marina Kriajevska Eugene Tulchinsky |
| author_facet | Mirko Terragno Anastassiya Vetrova Oleg Semenov A. Emre Sayan Marina Kriajevska Eugene Tulchinsky |
| author_sort | Mirko Terragno |
| collection | DOAJ |
| description | Abstract Triple-negative breast cancer (TNBC) is a difficult-to-treat, aggressive cancer type. TNBC is often associated with the cellular program of epithelial-mesenchymal transition (EMT) that confers drug resistance and metastasis. EMT and reverse mesenchymal-epithelial transition (MET) programs are regulated by several signaling pathways which converge on a group of transcription factors, EMT- TFs. Therapy approaches could rely on the EMT reversal to sensitise mesenchymal tumours to compounds effective against epithelial cancers. Here, we show that the antimalarial ROS-generating compound artesunate (ART) exhibits higher cytotoxicity in epithelial than mesenchymal breast cancer cell lines. Ectopic expression of EMT-TF ZEB1 in epithelial or ZEB1 depletion in mesenchymal cells, respectively, reduced or increased ART-generated ROS levels, DNA damage and apoptotic cell death. In epithelial cells, ZEB1 enhanced expression of superoxide dismutase 2 (SOD2) and glutathione peroxidase 8 (GPX8) implicated in ROS scavenging. Although SOD2 or GPX8 levels were unaffected in mesenchymal cells in response to ZEB1 depletion, stable ZEB1 knockdown enhanced total ROS. Receptor tyrosine kinase AXL maintains a mesenchymal phenotype and is overexpressed in TNBC. The clinically-relevant AXL inhibitor TP-0903 induced MET and synergised with ART to generate ROS, DNA damage and apoptosis in TNBC cells. TP-0903 reduced the expression of GPX8 and SOD2. Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds can have therapeutic prospects for TNBC treatment. |
| first_indexed | 2024-03-08T16:20:33Z |
| format | Article |
| id | doaj.art-8915a0f563694b62a9a34562c13ace7f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-08T16:20:33Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-8915a0f563694b62a9a34562c13ace7f2024-01-07T12:25:00ZengNature PortfolioScientific Reports2045-23222024-01-0114111210.1038/s41598-023-50710-3Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunateMirko Terragno0Anastassiya Vetrova1Oleg Semenov2A. Emre Sayan3Marina Kriajevska4Eugene Tulchinsky5Department of Biomedical Sciences, School of Medicine, Nazarbayev UniversityDepartment of Biomedical Sciences, School of Medicine, Nazarbayev UniversityRegulation of Gene Expression Laboratory, Institute of Cytology RASCancer Sciences Division, University of SouthamptonDepartment of Biomedical Sciences, School of Medicine, Nazarbayev UniversityDepartment of Biomedical Sciences, School of Medicine, Nazarbayev UniversityAbstract Triple-negative breast cancer (TNBC) is a difficult-to-treat, aggressive cancer type. TNBC is often associated with the cellular program of epithelial-mesenchymal transition (EMT) that confers drug resistance and metastasis. EMT and reverse mesenchymal-epithelial transition (MET) programs are regulated by several signaling pathways which converge on a group of transcription factors, EMT- TFs. Therapy approaches could rely on the EMT reversal to sensitise mesenchymal tumours to compounds effective against epithelial cancers. Here, we show that the antimalarial ROS-generating compound artesunate (ART) exhibits higher cytotoxicity in epithelial than mesenchymal breast cancer cell lines. Ectopic expression of EMT-TF ZEB1 in epithelial or ZEB1 depletion in mesenchymal cells, respectively, reduced or increased ART-generated ROS levels, DNA damage and apoptotic cell death. In epithelial cells, ZEB1 enhanced expression of superoxide dismutase 2 (SOD2) and glutathione peroxidase 8 (GPX8) implicated in ROS scavenging. Although SOD2 or GPX8 levels were unaffected in mesenchymal cells in response to ZEB1 depletion, stable ZEB1 knockdown enhanced total ROS. Receptor tyrosine kinase AXL maintains a mesenchymal phenotype and is overexpressed in TNBC. The clinically-relevant AXL inhibitor TP-0903 induced MET and synergised with ART to generate ROS, DNA damage and apoptosis in TNBC cells. TP-0903 reduced the expression of GPX8 and SOD2. Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds can have therapeutic prospects for TNBC treatment.https://doi.org/10.1038/s41598-023-50710-3 |
| spellingShingle | Mirko Terragno Anastassiya Vetrova Oleg Semenov A. Emre Sayan Marina Kriajevska Eugene Tulchinsky Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate Scientific Reports |
| title | Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate |
| title_full | Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate |
| title_fullStr | Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate |
| title_full_unstemmed | Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate |
| title_short | Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate |
| title_sort | mesenchymal epithelial transition and axl inhibitor tp 0903 sensitise triple negative breast cancer cells to the antimalarial compound artesunate |
| url | https://doi.org/10.1038/s41598-023-50710-3 |
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