TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis.
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.
Safina
A
A
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Ren
M-Q
MQ
Vandette
E
E
Bakin
A V
AV
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000556:secondary*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D015674:Mammary Neoplasms, Animal / Q000201:enzymology* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000502:physiology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7