Research Papers:

Opposite regulation of MDM2 and MDMX expression in acquisition of mesenchymal phenotype in benign and cancer cells

Eva Slabáková _, Gvantsa Kharaishvili, Monika Smějová, Zuzana Pernicová, Tereza Suchánková, Ján Remšík, Stanislav Lerch, Nicol Straková, Jan Bouchal, Milan Král, Zoran Culig, Alois Kozubík and Karel Souček

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Oncotarget. 2015; 6:36156-36171. https://doi.org/10.18632/oncotarget.5392

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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

Correspondence to:

Karel Souček, e-mail: [email protected]

Eva Slabáková, e-mail: [email protected]

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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