Activin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanisms

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dc.contributor.authorPanopoulou, E.en
dc.contributor.authorMurphy, C.en
dc.contributor.authorRasmussen, H.en
dc.contributor.authorBagli, E.en
dc.contributor.authorRofstad, E. K.en
dc.contributor.authorFotsis, T.en
dc.date.accessioned2015-11-24T19:38:10Z
dc.date.available2015-11-24T19:38:10Z
dc.identifier.issn0008-5472-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/24117
dc.rightsDefault Licence-
dc.subjectActivin Receptors/metabolismen
dc.subjectActivins/*therapeutic useen
dc.subjectAngiogenesis Inhibitors/*therapeutic useen
dc.subjectAnimalsen
dc.subjectAntineoplastic Agents/*therapeutic useen
dc.subjectCell Cycle Proteins/metabolismen
dc.subjectCell Movement/drug effectsen
dc.subjectCell Proliferation/drug effectsen
dc.subjectCyclin-Dependent Kinase Inhibitor p15en
dc.subjectCyclin-Dependent Kinase Inhibitor p21en
dc.subjectCyclin-Dependent Kinase Inhibitor p27en
dc.subjectDNA-Binding Proteins/metabolismen
dc.subjectEndothelial Cells/*drug effects/metabolismen
dc.subjectFemaleen
dc.subject*Gene Expression Regulation, Neoplasticen
dc.subjectHumansen
dc.subjectInhibin-beta Subunits/*therapeutic useen
dc.subjectMiceen
dc.subjectMice, Inbred BALB Cen
dc.subjectMice, Nudeen
dc.subjectNeovascularization, Pathologicen
dc.subjectNeuroblastoma/metabolism/pathology/*prevention & controlen
dc.subject*Signal Transductionen
dc.subjectSmad2 Proteinen
dc.subjectSmad3 Proteinen
dc.subjectTrans-Activators/metabolismen
dc.subjectTumor Cells, Cultureden
dc.subjectTumor Suppressor Proteins/metabolismen
dc.subjectVascular Endothelial Growth Factor Receptor-2/metabolismen
dc.subjectXenograft Model Antitumor Assaysen
dc.titleActivin A suppresses neuroblastoma xenograft tumor growth via antimitotic and antiangiogenic mechanismsen
heal.abstractThe tumor suppressor function of activin A, together with our findings that activin A is an inhibitor of angiogenesis, which is down-regulated by the N-MYC oncogene, prompted us to investigate in more detail its role in the malignant transformation process of neuroblastomas. Indeed, neuroblastoma cells with restored activin A expression exhibited a diminished proliferation rate and formed smaller xenograft tumors with reduced vascularity, whereas lung metastasis rate remained unchanged. In agreement with the decreased vascularity of the xenograft tumors, activin A inhibited several crucial angiogenic responses of cultured endothelial cells, such as proteolytic activity, migration, and proliferation. Endothelial cell proliferation, activin A, or its constitutively active activin receptor-like kinase 4 receptor (ALK4T206D), increased the expression of CDKN1A (p21), CDKN2B (p15), and CDKN1B (p27) CDK inhibitors and down-regulated the expression of vascular endothelial growth factor receptor-2, the receptor of a key angiogenic factor in cancer. The constitutively active forms of SMAD2 and SMAD3 were both capable of inhibiting endothelial cell proliferation, whereas the dominant-negative forms of SMAD3 and SMAD4 released the inhibitory effect of activin A on endothelial cell proliferation by only 20%. Thus, the effects of activin A on endothelial cell proliferation seem to be conveyed via the ALK4/SMAD2-SMAD3 pathways, however, non-SMAD cascades may also contribute. These results provide novel information regarding the role of activin A in the malignant transformation process of neuroblastomas and the molecular mechanisms involved in regulating angiogenesis thereof.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primary10.1158/0008-5472.CAN-04-2828-
heal.identifier.secondaryhttp://www.ncbi.nlm.nih.gov/pubmed/15753386-
heal.identifier.secondaryhttp://cancerres.aacrjournals.org/content/65/5/1877.full.pdf-
heal.journalNameCancer Resen
heal.journalTypepeer-reviewed-
heal.languageen-
heal.publicationDate2005-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικήςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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