Betaglycan alters NFκB-TGFß2 cross talk to reduce survival of human granulosa tumor cells.
Mol Endocrinol
; 27(3): 466-79, 2013 Mar.
Article
em En
| MEDLINE
| ID: mdl-23322721
ABSTRACT
The molecular pathways controlling granulosa cell tumor (GCT) survival are poorly understood. In many cell types, nuclear factor-κB (NFκB) and TGFß coordinately regulate cell survival to maintain tissue homeostasis. Because GCT cell lines exhibit constitutively activated NFκB, we hypothesized that NFκB blocks TGFß-mediated cell death in GCT cells. To test this hypothesis, we used the human GCT cell line KGN, which exhibits loss of betaglycan, a TGFß co-receptor. After inhibition of NFκB in KGN cells, re-expression of betaglycan resulted in a decrease in cell viability, which was further decreased by TGFß2. Intriguingly, TGFß2 increased NFκB reporter activity in control cells, but betaglycan expression suppressed both basal and TGFß2-stimulated NFκB activity. Chemical inhibition of Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signaling or SMAD2/3 gene silencing revealed that both SMADs contributed to cell survival. Furthermore, inhibiting NFκB activity resulted in a specific reduction in SMAD3 expression. Conversely, overexpression of SMAD3 increased basal NFκB activity and countered betaglycan-mediated suppression of NFκB activity. Finally, ERK1/2 activation emerged as the point of convergence of NFκB, SMAD3, and TGFß2/betaglycan governance of GCT cell viability. Key findings in KGN cells were reproduced in a second GCT cell line, COV434. Collectively, our data establish that both SMAD2/3 and NFκB signaling pathways support GCT cell viability and suggest the existence of a positive feedback loop between NFκB and SMAD3 signaling in late-stage GCT. Furthermore, our data suggest that loss of betaglycan during tumor progression in GCT alters the functional outcomes generated by NFκB and TGFß pathway cross talk.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteoglicanas
/
NF-kappa B
/
Receptores de Fatores de Crescimento Transformadores beta
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Fator de Crescimento Transformador beta2
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Tumor de Células da Granulosa
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Mol Endocrinol
Assunto da revista:
BIOLOGIA MOLECULAR
/
ENDOCRINOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Austrália