TAK1 activation for cytokine synthesis and proliferation of endometriotic cells.
ABSTRACT Endometriosis causes pelvic pain and infertility in women of reproductive age. We explored TNFalpha-induced specific signaling pathways and gene expressions in endometriotic stromal cells (ESCs). Based on the data of the pathway specific cDNA array, we analyzed the role of TAK1, which is believed to work as a common mediator for NF-kappaB and MAPK pathways. Using the NF-kappaB pathway array, we found that TNFalpha upregulated ICAM-3, IL-6, IL-8, TAK1, JNK2, RelA, and TLR4 expressions. TNFalpha augmented the phosphorylation of TAK1. By transfection of TAK1 siRNA, TNFalpha-induced phosphorylation of IkappaBalpha, JNK1/2, and p38MAPK, as well as IL-6 or IL-8 expression, were repressed. TAK1 silencing in TNFalpha-pretreated ESCs caused a decrease in the proportion of cells in S-phase, and reduced TNFalpha-promoted BrdU incorporation. We provide the first evidence that TNFalpha and its downstream TAK1, which are key mediators for NF-kappaB and MAPK pathways, may be involved in the pathogenesis of endometriosis.
SourceAvailable from: David W Chan[Show abstract] [Hide abstract]
ABSTRACT: Transforming growth factor (TGF)-β-activating kinase 1 (TAK1) is a serine/threonine kinase which is frequently associated with human cancer progression. However, its functional role in tumorigenesis is still controversial. Here, we report that TAK1 enhances the oncogenic capacity of ovarian cancer cells through the activation of NF-κB signaling. We found that TAK1 is frequently upregulated and significantly associated with high-grade and metastatic ovarian cancers. Mechanistic studies showed that Ser412 phosphorylation is required for TAK1 in activating NF-κB signaling and promotes aggressiveness of ovarian cancer cells. Conversely, suppression of TAK1 activity by point mutation at Ser412, RNAi mediated gene knockdown or TAK1 specific inhibitor ((5Z) -7-Oxozeaenol) remarkably impairs tumor growth and metastasis in ovarian cancer in vitro and in vivo. Our study underscores the importance of targeting TAK1 as a promising therapeutic approach to counteract the ovarian cancer progression.Oncotarget 09/2014; 5(17):7549-62. · 6.63 Impact Factor
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ABSTRACT: Tumor necrosis factor-α (TNF-α) has multiple effects on proliferation and differentiation of hMSCs. TAK1 mediates activation of nuclear factor-kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and p38 pathways in response to TNF-α. However, the role of TAK1 in TNF- α-induced effects in hADSCs and its signaling pathway has not been clearly defined. Therefore, this study was designated to clarify the role of TAK1 in TNF-α induced actions on proliferation and differentiation of hADSCs and its downstream signaling pathway. Inhibiting TAK1 expression inhibited the TNF-α-induced increase in osteogenic differentiation and basal osteogenic differentiation without affecting the TNF-α-induced effect on proliferation and adipogenic differentiation of hADSCs. A western blot analysis showed that TNF-α treatment induced degradation of IκB, but that TAK1 siRNA transfection did not protect against TNF-α-induced IκB degradation. The transfection of TAK1 siRNA also did not affect TNF-α induced IκB phosphorylation or ERK1/2 phosphorylation. However, downregulating TAK1 inhibited this TNF-α-induced S536 phosphorylation of the p65 subunit. TNF-α treatment induced p38 phosphorylation, which was inhibited by the transfection of TAK1 siRNA. Adding p38 inhibitor inhibited TNF-α-induced p65 phosphorylation, NF-κB promoter activity and TNF-α-induced increase in osteogenic differentiation of hADSCs. These data indicate that TAK1 is involved in the TNF-α-induced activation of p38 kinase, which subsequently phosphorylates the NF-κB p65 subunit, and increases the transactivation potential of p65 and osteogenic differentiation in hADSCs.Stem Cells and Development 10/2014; 24(7). DOI:10.1089/scd.2014.0272 · 4.20 Impact Factor
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ABSTRACT: What is the role of the inhibitor of apoptosis proteins (IAPs) in human endometriotic tissues and a mouse model of endometriosis?Human Reproduction 11/2014; DOI:10.1093/humrep/deu288 · 4.59 Impact Factor