Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells
Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)–specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurr...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-12-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523314000953 |
| _version_ | 1811276988556509184 |
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| author | Florian Kopp Adam Hermawan Prajakta Shirish Oak Vijay Kumar Ulaganathan Annika Herrmann Nefertiti Elnikhely Chitra Thakur Zhiguang Xiao Pjotr Knyazev Beyhan Ataseven Rajkumar Savai Ernst Wagner Andreas Roidl |
| author_facet | Florian Kopp Adam Hermawan Prajakta Shirish Oak Vijay Kumar Ulaganathan Annika Herrmann Nefertiti Elnikhely Chitra Thakur Zhiguang Xiao Pjotr Knyazev Beyhan Ataseven Rajkumar Savai Ernst Wagner Andreas Roidl |
| author_sort | Florian Kopp |
| collection | DOAJ |
| description | Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)–specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition. |
| first_indexed | 2024-04-13T00:07:35Z |
| format | Article |
| id | doaj.art-0c322b1633a64b86881e9a981c54fddf |
| institution | Directory Open Access Journal |
| issn | 1936-5233 1944-7124 |
| language | English |
| last_indexed | 2024-04-13T00:07:35Z |
| publishDate | 2014-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-0c322b1633a64b86881e9a981c54fddf2022-12-22T03:11:11ZengElsevierTranslational Oncology1936-52331944-71242014-12-017670271110.1016/j.tranon.2014.09.002Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor CellsFlorian Kopp0Adam Hermawan1Prajakta Shirish Oak2Vijay Kumar Ulaganathan3Annika Herrmann4Nefertiti Elnikhely5Chitra Thakur6Zhiguang Xiao7Pjotr Knyazev8Beyhan Ataseven9Rajkumar Savai10Ernst Wagner11Andreas Roidl12Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, GermanyDepartment of Molecular Biology, “Cancer Metastasis Group”, Max-Planck Institute of Biochemistry, Martinsried, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, GermanyMolecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Bad Nauheim, GermanyDepartment of Molecular Biology, “Cancer Metastasis Group”, Max-Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Gynecology and Obstetrics, Rotkreuzklinikum Munich, GermanyMolecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Bad Nauheim, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, GermanyAcquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)–specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition.http://www.sciencedirect.com/science/article/pii/S1936523314000953 |
| spellingShingle | Florian Kopp Adam Hermawan Prajakta Shirish Oak Vijay Kumar Ulaganathan Annika Herrmann Nefertiti Elnikhely Chitra Thakur Zhiguang Xiao Pjotr Knyazev Beyhan Ataseven Rajkumar Savai Ernst Wagner Andreas Roidl Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells Translational Oncology |
| title | Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells |
| title_full | Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells |
| title_fullStr | Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells |
| title_full_unstemmed | Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells |
| title_short | Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells |
| title_sort | sequential salinomycin treatment results in resistance formation through clonal selection of epithelial like tumor cells |
| url | http://www.sciencedirect.com/science/article/pii/S1936523314000953 |
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