title: Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: M A
authors.initials: MA
authors.lastname: Hoda
authors.forename: J
authors.initials: J
authors.lastname: Münzker
authors.forename: B
authors.initials: B
authors.lastname: Ghanim
authors.forename: K
authors.initials: K
authors.lastname: Schelch
authors.forename: T
authors.initials: T
authors.lastname: Klikovits
authors.forename: V
authors.initials: V
authors.lastname: Laszlo
authors.forename: E
authors.initials: E
authors.lastname: Sahin
authors.forename: A
authors.initials: A
authors.lastname: Bedeir
authors.forename: A
authors.initials: A
authors.lastname: Lackner
authors.forename: B
authors.initials: B
authors.lastname: Dome
authors.forename: U
authors.initials: U
authors.lastname: Setinek
authors.forename: M
authors.initials: M
authors.lastname: Filipits
authors.forename: M
authors.initials: M
authors.lastname: Eisenbauer
authors.forename: I
authors.initials: I
authors.lastname: Kenessey
authors.forename: S
authors.initials: S
authors.lastname: Török
authors.forename: T
authors.initials: T
authors.lastname: Garay
authors.forename: B
authors.initials: B
authors.lastname: Hegedus
authors.forename: A
authors.initials: A
authors.lastname: Catania
authors.forename: S
authors.initials: S
authors.lastname: Taghavi
authors.forename: W
authors.initials: W
authors.lastname: Klepetko
authors.forename: W
authors.initials: W
authors.lastname: Berger
authors.forename: M
authors.initials: M
authors.lastname: Grusch
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D056741:Cyclin D / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D056741:Cyclin D; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C422405:activin A; D028341:Activins