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

M. A. Hoda, J. Münzker, B. Ghanim, K. Schelch, T. Klikovits, V. Laszlo, E. Sahin, A. Bedeir, A. Lackner, B. Dome, U. Setinek, M. Filipits, M. Eisenbauer, I. Kenessey, S. Török, T. Garay, B. Hegedus, A. Catania, S. Taghavi, W. KlepetkoW. Berger, M. Grusch

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1978-1986
Number of pages9
JournalBritish Journal of Cancer
Volume107
Issue number12
DOIs
Publication statusPublished - Dec 4 2012

Keywords

  • activin
  • activin receptor
  • mesothelioma
  • SMAD signalling
  • targeted therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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