MDM2 and MDMX in prostate cancer - associated EMT: expression, localization and effect on cell migration

Most cancer-related deaths are associated with advanced disease and metastasis. Epithelial-mesenchymal transition (EMT), in which epithelial cells lose their polarity and become motile mesenchymal cells, is viewed as an essential step facilitating dissemination of tumor cells. While the EMT-inducing transcription factors from the Snail, Twist and ZEB families are important mediators of cancer progression and metastasis, reports about expression of MDM2 and MDMX in cancer cells and metastases are conflicting.

Apart from being a crucial regulator of the p53 tumor suppressor, MDM2 cooperates with p53 in negative regulation of an EMT-inducing transcription factor SNAI 2/Slug, implying that MDM2 can function as a regulator in the EMT process. Analyzing paired benign and tumorigenic cell lines derived from prostate and breast tissue, we observed that cancer transformation is accompanied by EMT, downregulation of MDM2 expression and upregulation of MDMX. Moreover, the same trend was observed in a proportion of patient prostate tissues obtained from primary tumors and their respective metastases. The EMT status was evaluated based on the expression of epithelial markers E-cadherin and ?-catenin and mesenchymal markers vimentin and Slug.

In vitro migration experiments using prostate cancer cell lines show that the effect of MDM2 expression on cell migration is cell type specific. While overexpression of MDM2 led to a moderate inhibition of cell migration in BPH-1 CAFTD03, opposite effect was observed in DU145, and no change in migration potential was detected in PC3 cells. In order to explain the differences in migration phenotype, we studied subcellular localization of both endogenous and overexpressed MDM2 and MDMX. Our data suggest that nuclear localization of both MDM2 and MDMX correlates with anti-migratory properties of overexpressed MDM2.

Altogether, our data demonstrate an association of the EMT phenotype with deregulation of two important regulators of the p53 tumor suppressor, MDM2 and MDMX, which leads to context-dependent changes in cell behaviour. 

This work was supported by grant no. P301/12/P407 of the Czech Science Foundation; by grant no. NT13573-4/2012 of the Ministry of Health of the Czech Republic; by the Academy of Sciences of the Czech Republic, grant no. AV0Z50040702, and by the project FNUSA-ICRC no. CZ.1.05/1.1.00/02.0123 from the European Regional Development Fund.