title: Rat mesothelioma cell proliferation requires p38δ mitogen activated protein kinase and C/EBP-α.
abstract: Pleural malignant mesothelioma is a rare but deadly tumour mainly induced by asbestos inhalation. Despite the ban of asbestos in 1990 in 52 countries, mesothelioma cases still increase worldwide. In pleural mesothelioma, p38 mitogen activated protein kinases (MAPK) have been suggested to play a major role in carcinogenesis and aggressiveness of tumours. The aim of this study was to determine the role of the different four p38 MAPK isoforms and their effect on proliferation together with the underlying signalling pathways in a rat pleural mesothelioma cell line. Rat pleural mesothelioma cells were stimulated with platelet-derived growth factor (PDGF)-BB and/or transforming growth factor beta (TGF)-β. MAPK and transcription factor expression and activation was monitored in the cytosol and nucleus by immuno-blotting. Proliferation was determined by manual cell count and siRNAs were used to control MAPK and transcription factor expression and action. Only PDGF-BB, but not TGF-β1 induced proliferation via activated Erk1/2 and p38 MAPK. The p38α and δ isoforms were expressed in the cytosol, and upon activation p38δ translocated into the nucleus, while p38α remained in the cytosol. No other p38 isoform was expressed by rat mesothelioma cells. C/EBP-α was found in both the cytosol and the nucleus, while C/EBP-β was not expressed at all. PDGF-BB induced proliferation was suppressed by down-regulation of either Erk1/2, or p38δ MAPK, or C/EBP-α. Furthermore, TGF-β inhibited PDGF-BB induced proliferation by interruption of p38 MAPK signalling. From this rat model, we conclude that in pleural mesothelioma, p38δ in C/EBP-α mediate proliferation and thus may represent new targets in mesothelioma therapy.
authors.affiliation: Pulmonary Cell Research, Department Biomedicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhong
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.forename: John
authors.initials: J
authors.lastname: Szilard
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D000818:Animals; D000077214:Becaplermin; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015870:Gene Expression; D008654:Mesothelioma / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D010997:Pleural Neoplasms / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D011916:Rats, Inbred F344; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases