Inhibition of transforming growth factor-β-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasis.
BACKGROUND
Tumour cell metastasis involves cell adhesion and invasion, processes that depend on signal transduction, which can be influenced by the tumour microenvironment. N-6 polyunsaturated fatty acids, found both in the diet and in response to inflammatory responses, are important components of this microenvironment.


METHODS
We used short hairpin RNA (shRNA) knockdown of TGF-β-activated kinase-1 (TAK1) in human tumour cells to examine its involvement in fatty acid-stimulated cell adhesion and invasion in vitro. An in vivo model of metastasis was developed in which cells, stably expressing firefly luciferase and either a control shRNA or a TAK1-specific shRNA, were injected into the mammary fat pads of mice fed diets, rich in n-6 polyunsaturated fatty acids. Tumour growth and spontaneous metastasis were monitored with in vivo and in situ imaging of bioluminescence.


RESULTS
Arachidonic acid activated TAK1 and downstream kinases in MDA-MB-435 breast cancer cells and led to increased adhesion and invasion. Knockdown of TAK1 blocked this activation and inhibited both cell adhesion and invasion in vitro. Tumour growth at the site of injection was not affected by TAK1 knockdown, but both the incidence and extent of metastasis to the lung were significantly reduced in mice injected with TAK1 knockdown cells compared with mice carrying control tumour cells.


CONCLUSIONS
These data demonstrate the importance of TAK1 signalling in tumour metastasis in vivo and suggest an opportunity for antimetastatic therapies.
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, Mail Drop D2-05, Room D248A, Rall Building, 111T. W. Alexander Drive, Research Triangle Park, NC 27709, USA.
D M
DM
Ray
P H
PH
Myers
J T
JT
Painter
M J
MJ
Hoenerhoff
K
K
Olden
J D
JD
Roberts
D000818:Animals; D016718:Arachidonic Acid; D001943:Breast Neoplasms; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D016718:Arachidonic Acid; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D000099151:MAP Kinase Kinase Kinase 7