Opposite regulation of MDM2 and MDMX expression in acquisition of mesenchymal phenotype in benign and cancer cells
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Eva Slabáková1,2, Gvantsa Kharaishvili3, Monika Smějová1,4, Zuzana Pernicová1,2, Tereza Suchánková1, Ján Remšík1,2,5, Stanislav Lerch1,5, Nicol Straková1,2, Jan Bouchal3, Milan Král6, Zoran Culig2,7, Alois Kozubík1,5, Karel Souček1,2,5
1Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic
2Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czech Republic
3Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
4Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
5Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
6Department of Urology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
7Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria
Karel Souček, e-mail: firstname.lastname@example.org
Eva Slabáková, e-mail: email@example.com
Keywords: epithelial-mesenchymal transition, MDM2/MDMX, SNAI2/SLUG, TWIST, prostate/breast cancer
Received: July 28, 2015 Accepted: September 15, 2015 Published: September 25, 2015
Plasticity of cancer cells, manifested by transitions between epithelial and mesenchymal phenotypes, represents a challenging issue in the treatment of neoplasias. Both epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are implicated in the processes of metastasis formation and acquisition of stem cell-like properties. Mouse double minute (MDM) 2 and MDMX are important players in cancer progression, as they act as regulators of p53, but their function in EMT and metastasis may be contradictory. Here, we show that the EMT phenotype in multiple cellular models and in clinical prostate and breast cancer samples is associated with a decrease in MDM2 and increase in MDMX expression. Modulation of EMT-accompanying changes in MDM2 expression in benign and transformed prostate epithelial cells influences their migration capacity and sensitivity to docetaxel. Analysis of putative mechanisms of MDM2 expression control demonstrates that in the context of defective p53 function, MDM2 expression is regulated by EMT-inducing transcription factors Slug and Twist. These results provide an alternative context-specific role of MDM2 in EMT, cell migration, metastasis, and therapy resistance.
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