Thursday, November 22, 2012

From U Vienna: Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells

http://www.ncbi.nlm.nih.gov/pubmed/23169291


 2012 Nov 20. doi: 10.1038/bjc.2012.519. [Epub ahead of print]

Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells.

Source

1] Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria [2] Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna 1090, Austria.

Abstract

Background:Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM).Methods:The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed.Results:Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression.Conclusion:Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.

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