Document Detail

TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis.
MedLine Citation:
PMID:  17828308     Owner:  NLM     Status:  MEDLINE    
Transforming growth factor-beta 1 (TGF-beta1) 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-beta1 responses, the mechanism of its regulation is not well understood. Here, we present evidence that TGF-beta-activated protein kinase 1 (TAK1) is critical for TGF-beta 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-kappaB signaling. Dn-TAK1 reduces NF-kappaB transcriptional response and inhibition of NF-kappaB reduces expression of MMP-9 and activity of the MMP-9 promoter reporter. Together, these findings suggest that TAK1 contributes to TGF-beta1-mediated tumor angiogenesis and metastasis via a mechanism involving the TAK1-NF-kappaB-MMP-9 pathway.
A Safina; M-Q Ren; E Vandette; A V Bakin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-09-10
Journal Detail:
Title:  Oncogene     Volume:  27     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-21     Completed Date:  2008-03-12     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  1198-207     Citation Subset:  IM    
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
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MeSH Terms
Cell Line, Tumor
Lung Neoplasms / enzymology*,  pathology,  secondary*
MAP Kinase Kinase Kinases / antagonists & inhibitors,  genetics,  physiology*
MAP Kinase Signaling System / genetics,  physiology
Mammary Neoplasms, Animal / enzymology*,  pathology
Matrix Metalloproteinase 9 / metabolism*,  physiology
Mice, SCID
NF-kappa B / physiology
Neoplasm Transplantation
Neovascularization, Pathologic / enzymology
Transforming Growth Factor beta1 / physiology*
Grant Support
Reg. No./Substance:
0/NF-kappa B; 0/Transforming Growth Factor beta1; EC Kinase Kinase Kinases; EC kinase kinase kinase 7; EC Metalloproteinase 9

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