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.