Abstract
Transforming growth factor-β 1 (TGF-β1) signaling in tumor cells has been implicated in tumor angiogenesis and metastasis by regulating matrix proteolysis. Although MMP-9/gelatinase-B is an important component of these TGF-β1 responses, the mechanism of its regulation is not well understood. Here, we present evidence that TGF-β-activated protein kinase 1 (TAK1) is critical for TGF-β regulation of MMP-9 and the metastatic potential of breast cancer cell line MDA-MB-231. We found that suppression of TAK1 signaling by dominant-negative (dn) TAK1 or RNA interference (siRNA) reduces expression of MMP-9 and tumor cell invasion, without growth inhibition in cell culture. The orthotopic xenograft studies in SCID mice showed that suppression of TAK1 signaling by dn-TAK1 reduces tumor growth and formation of lung metastases. Dn-TAK1 reduced the proliferation Ki-67 index and neovasculature of orthotopic xenografts. TAK1-mediated regulation of MMP-9 involves NF-κB signaling. Dn-TAK1 reduces NF-κB transcriptional response and inhibition of NF-κB reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-β1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-κB-MMP-9 pathway.
Original language | English (US) |
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Pages (from-to) | 1198-1207 |
Number of pages | 10 |
Journal | Oncogene |
Volume | 27 |
Issue number | 9 |
DOIs | |
State | Published - Feb 21 2008 |
Externally published | Yes |
Keywords
- Angiogenesis
- Invasion
- MMP-9
- Metastasis
- TAK1
- TGF-β
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research