title: Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells.
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.
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kopp
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Hermawan
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Prajakta Shirish
authors.initials: PS
authors.lastname: Oak
authors.affiliation: Department of Molecular Biology, "Cancer Metastasis Group", Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Ulaganathan
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Herrmann
authors.affiliation: Molecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Nefertiti
authors.initials: N
authors.lastname: Elnikhely
authors.affiliation: Department of Molecular Biology, "Cancer Metastasis Group", Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Chitra
authors.initials: C
authors.lastname: Thakur
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Pjotr
authors.initials: P
authors.lastname: Knyazev
authors.affiliation: Department of Gynecology and Obstetrics, Rotkreuzklinikum Munich, Germany.
authors.forename: Beyhan
authors.initials: B
authors.lastname: Ataseven
authors.affiliation: Molecular Mechanisms in Lung Cancer, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.affiliation: Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: andreas.roidl@cup.uni-muenchen.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roidl