title: Betaglycan alters NFκB-TGFβ2 cross talk to reduce survival of human granulosa tumor cells.
abstract: The molecular pathways controlling granulosa cell tumor (GCT) survival are poorly understood. In many cell types, nuclear factor-κB (NFκB) and TGFβ coordinately regulate cell survival to maintain tissue homeostasis. Because GCT cell lines exhibit constitutively activated NFκB, we hypothesized that NFκB blocks TGFβ-mediated cell death in GCT cells. To test this hypothesis, we used the human GCT cell line KGN, which exhibits loss of betaglycan, a TGFβ 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 TGFβ2. Intriguingly, TGFβ2 increased NFκB reporter activity in control cells, but betaglycan expression suppressed both basal and TGFβ2-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 TGFβ2/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 TGFβ pathway cross talk.
authors: Prince Henry’s Institute, Department of Developmental Biology and Anatomy, Monash University, Clayton, Victoria 3168, Australia. maree.bilandzic@princehenrys.org
authors: Maree
authors: M
authors: Bilandzic
authors: Simon
authors: S
authors: Chu
authors: Yao
authors: Y
authors: Wang
authors: Han L
authors: HL
authors: Tan
authors: Peter J
authors: PJ
authors: Fuller
authors: Jock K
authors: JK
authors: Findlay
authors: Kaye L
authors: KL
authors: Stenvers
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006106:Granulosa Cell Tumor / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053781:Transforming Growth Factor beta2; C071736:betaglycan; D048049:Extracellular Signal-Regulated MAP Kinases