Paclitaxel resistance is mediated by NF-κB on mesenchymal primary breast cancer cells |
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Authors: | José Esparza-Ló pez,Ossian Longoria,Eliseo Neftali De La Cruz-Escobar,Julio Cesar Garibay-Dí az,Eucario Leó n-Rodrí guez,Marí a De Jesú s Ibarra-Sá nchez |
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Affiliation: | 1.Biochemistry Unit, Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico;2.Research Support Network, National Autonomous University of Mexico-Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico;3.Hematology and Oncology Department, Salvador Zubirán National Institute of Health Sciences and Nutrition, Mexico City 14080, Mexico |
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Abstract: | Paclitaxel has been used widely to treat breast cancer and other types of cancer. However, resistance is a major cause of failure for treatment and results in cancer progression. The present study investigated the association between paclitaxel resistance and the mesenchymal phenotype, using a model of primary breast cancer cells and employing four different cultures, two with an epithelial phenotype (MBCDF and MBCD17) and two with a mesenchymal phenotype (MBCDF-D5 and MBCD3). Epithelial-mesenchymal markers were evaluated by western blotting; MBCDF and MBCD17 cells expressed E-cadherin, SNAIL, Slug, and Twist, low levels of N-cadherin, but not vimentin. MBCDF-D5 and MBCD3 cells expressed N-cadherin, vimentin, and higher levels of SNAIL, and low levels of E-cadherin, Slug, and Twist. Cell viability was evaluated using a crystal violet assay after paclitaxel treatment; primary breast cancer cells with mesenchymal phenotype were resistant to paclitaxel compared with the epithelial primary breast cancer cells. Furthermore, using western blotting, it was revealed that mesenchymal cells had elevated levels of nuclear factor-κΒ (NF-κB) p65 and IκB kinase (IKK). Additionally, it was demonstrated that paclitaxel-induced degradation of the inhibitor of NF-κB, activation of NF-κB in a dose-dependent manner, and Bcl-2 and Bcl-xL upregulation. Finally, employing western blotting and crystal violet assays, the effects of the proteasome inhibitor ALLN were assessed. ALLN inhibited paclitaxel-induced NF-κB activation and restored the sensitivity to paclitaxel. Together, these data suggest that targeting the NF-κB/IKK axis might be a promising strategy to overcome paclitaxel resistance. |
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Keywords: | breast cancer, paclitaxel, NF-κ B, mesenchymal phenotype |
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