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  Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells

Kopp, F., Hermawan, A., Oak, P. S., Ulaganathan, V. K., Herrmann, A., Elnikhely, N., et al. (2014). Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells. TRANSLATIONAL ONCOLOGY, 7(6), 702-711. doi:10.1016/j.tranon.2014.09.002.

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 Creators:
Kopp, Florian1, Author
Hermawan, Adam1, Author
Oak, Prajakta Shirish1, Author
Ulaganathan, Vijay Kumar1, Author
Herrmann, Annika1, Author
Elnikhely, Nefertiti1, Author
Thakur, Chitra1, Author
Xiao, Zhiguang2, Author              
Knyazev, Pjotr2, Author              
Ataseven, Beyhan1, Author
Savai, Rajkumar1, Author
Wagner, Ernst1, Author
Roidl, Andreas1, Author
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1external, ou_persistent22              
2Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565172              

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Free keywords: BREAST-CANCER CELLS; MIR-200 FAMILY; MESENCHYMAL TRANSITION; DOWN-REGULATION; DRUG-RESISTANCE; REPRESSORS ZEB1; UP-REGULATION; EMT; CISPLATIN; MIGRATION
 Abstract: 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.

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Language(s): eng - English
 Dates: 2014
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
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 Rev. Type: Peer
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Title: TRANSLATIONAL ONCOLOGY
Source Genre: Journal
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Publ. Info: 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA : ELSEVIER SCIENCE INC
Pages: - Volume / Issue: 7 (6) Sequence Number: - Start / End Page: 702 - 711 Identifier: ISSN: 1944-7124