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

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

doi:10.18632/oncotarget.5392

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.

Highlights

The metastatic process is a serious aspect of cancer disease that is tightly linked to cancer cell plasticity, epithelial-mesenchymal transition (EMT), mesenchymalepithelial transition (MET), and acquisition of a stem-like cell phenotype, resulting in cancer cell dissemination and resistance to therapy [1]
We have previously shown that SNAI2/Slug is an early factor upregulated in transforming growth factor (TGF)-β-induced EMT of benign prostate epithelial cells, which is later www.impactjournals.com/oncotarget accompanied by induction of zinc finger E-box binding homeobox (ZEB)1 and ZEB2 and deregulation of the miR200 family of microRNAs [4]
We observed that compared to epithelial benign prostatic hyperplasias (BPH)-1 cells, tumorigenic CAFTD03 cells, whose phenotype is shifted towards mesenchymal cells, were less sensitive to docetaxel, a microtubule inhibitor used in standard chemotherapy of metastatic CaP (Figure 1E)

Summary

Introduction

The metastatic process is a serious aspect of cancer disease that is tightly linked to cancer cell plasticity, epithelial-mesenchymal transition (EMT), mesenchymalepithelial transition (MET), and acquisition of a stem-like cell phenotype, resulting in cancer cell dissemination and resistance to therapy [1]. EMT and MET are reversible processes that enable cell detachment from the primary tumor, penetration and survival in the circulation, and formation of metastasis at a distant site [2]. Both transitions are regulated by cooperation between multiple transcription factors and microRNAs whose functions may be overlapping, and effect of individual molecules in these processes can be time- and/or context-dependent [3]. EMT can result from defects in a crucial tumor suppressor, p53 Both gain-of-function p53 mutations and p53 loss have been associated with EMT [7,8,9], while intact p53 function is important for maintenance of the epithelial phenotype [10, 11]. Inhibition of MDM2 was shown to sensitize various cancer cell lines to chemotherapy and the therapeutic strategy of p53 reactivation by MDM2 inhibitors and antagonists is being investigated in several clinical trials [14, 15]

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Results

Conclusion