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TAK1‐mediated stress signaling pathways are essential for TNF‐α‐promoted pulmonary metastasis of murine colon cancer cells
Author(s) -
Choo MinKyung,
Sakurai Hiroaki,
Koizumi Keiichi,
Saiki Ikuo
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21734
Subject(s) - cancer research , p38 mitogen activated protein kinases , metastasis , tumor necrosis factor alpha , mapk/erk pathway , signal transduction , microbiology and biotechnology , kinase , small interfering rna , biology , chemistry , medicine , transfection , immunology , cancer , cell culture , genetics
Abstract We have recently established a TNF‐α‐promoted metastasis model, in which the ability to metastasize to the lung was enhanced by stimulation of cultured colon 26 cells with TNF‐α before intravenous inoculation. To investigate intracellular events in metastatic cascades of TNF‐α‐treated cancer cells, we have focused on the stress signaling pathways to c‐Jun N ‐terminal kinase (JNK) and p38. Treatment with a specific inhibitor, SP600125 or SB203580, in vitro suppressed TNF‐α‐induced migration and pulmonary metastasis. Activation of endogenous TAK1, a mitogen‐activated protein kinase (MAP3K) regulating the JNK and p38 MAPK pathways, was induced rapidly by TNF‐α, and co‐transfection of TAK1 with its activator protein TAB1 stimulated activation of JNK and p38 MAPKs, which led to activation of the transcription factor AP‐1. The activation of stress signaling pathways by TAK1 resulted in enhanced migration to fibronectin in vitro and metastasis to the lung in vivo without affecting cell proliferation in vitro and tumor growth in vivo . Moreover, knockdown of endogenous TAK1 using small interfering RNA (siRNA) suppressed the TNF‐α‐induced JNK/p38 activation, migration and pulmonary metastasis. These results indicate that TAK1‐mediated stress signaling pathways in cancer cells are essential for TNF‐α‐promoted metastasis to the lung. © 2005 Wiley‐Liss, Inc.