title: Opposite regulation of MDM2 and MDMX expression in acquisition of mesenchymal phenotype in benign and cancer cells.
abstract: 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.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Slabáková
authors.affiliation: Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Gvantsa
authors.initials: G
authors.lastname: Kharaishvili
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Monika
authors.initials: M
authors.lastname: Smějová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Pernicová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Suchánková
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.|Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Ján
authors.initials: J
authors.lastname: Remšík
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Lerch
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
authors.forename: Nicol
authors.initials: N
authors.lastname: Straková
authors.affiliation: Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Bouchal
authors.affiliation: Department of Urology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Král
authors.affiliation: Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.|Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of The Czech Republic, v.v.i., Brno, Czech Republic.|Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.|Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Souček
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis*; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2/MDMX; SNAI2/SLUG; TWIST; epithelial-mesenchymal transition; prostate/breast cancer