Abstract
Malignant pleural mesothelioma (MM) resists all available anticancer therapies. A major pathology of MM is the uncontrolled cell proliferation and the fast local spreading with rare metastasis. Therefore the inhibition of proliferation is a major therapeutic target. Proliferation of MM cells was linked to mitogen activated protein kinase (MAPK) activity. In this study we characterised the regulation of MAPK regulated CCAAT/Enhancer binding proteins (C/EBP) and their role in MM cell proliferation. In five human MM cell lines, cytosolic and nuclear protein expression was determined by immuno-blotting and immuno-chemistry in tissue sections. Transcription of C/EBPs was determined by real time PCR and translation by a translation reporter assay. We observed a cell compartment specific expression pattern of p38-α, -β and -γ MAPK in MM cells. Erk1/2 and p38 MAPK together up-regulated the expression of C/EBP-β and -δ, while C/EBP-α was not expressed. Compared to mesothelial cells C/EBP-α translation was reduced in MM, while the mRNA was constitutively expressed. MM cells expressed a relative high level of the C/EBP-α translation suppressor calreticulin, while eIF4E was not significantly modified. Cell proliferation was inhibited by either the blockade of Erk1/2, or p38-β and -γ MAPK, or C/EBP-β. Transfection with a C/EBP-α expression vector reduced proliferation and increased the MM cell's sensitivity to steroids. Our data implies that in human MM cells an epigenetic mechanism deregulates the translation control of the cell differentiation factor C/EBP-α which leads to increased proliferation and drug resistance.
- © 2011 ERS