TAK1‐mediated stress signaling pathways are essential for TNF‐α‐promoted pulmonary metastasis of murine colon cancer cells

Abstract

We have recently established a TNF-a-promoted metastasis model, in which the ability to metastasize to the lung was enhanced by stimulation of cultured colon 26 cells with TNF-a before intravenous inoculation. To investigate intracellular events in metastatic cascades of TNF-a-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-a-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-a, 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-a-induced JNK/p38 activation, migration and pulmonary metastasis. These results indicate that TAK1-mediated stress signaling pathways in cancer cells are essential for TNF-a-promoted metastasis to the lung. ' 2005 Wiley-Liss, Inc.Key words: TAK1; TNF-a; metastasis; inflammation The theory of a functional relationship between inflammation and cancer is not new. Two millennia ago, the Greek doctor Galen noticed a link between inflammation and cancer, and Virchow hypothesized in 1863 that the origin of cancer was a site of chronic inflammation.1-3 Over the past 10 years, the relationship between inflammation and cancer has become more widely accepted. Inflammatory cells and cytokines found in tumors are more likely to contribute to tumor growth, progression and immunosuppression than they are to mount an effective host anti-tumor response.1-5 Therefore, inflammation is responsible for the development of cancers, in organs such as the liver, esophagus, stomach, large intestine and urinary bladder. The proinflammatory cytokine tumor necrosis factor-a (TNF-a) is a key mediator in inflammation. Despite the name, TNF-a is important in early events in tumorigenesis, regulating a cascade of cytokines, chemokines, adhesion molecules, extracellular proteases and proangiogenic molecules. 1,6 In fact, it has been demonstrated that TNF-a expression is increased in the serum of cancer patients.7,8 TNF-a also plays a critical role in tumor progression. Injection of TNF-a in mice results in an enhancement of metastasis accompanied by tumor cell extravasation with increased expression of adhesion molecules, in which the action of TNF-a is not distinguishable between host cells or cancer cells.9,10 Kitakata et al. demonstrated that the action of TNF-a toward host cells is essential for metastasis using TNF-RI-deficient mice. 11 We have recently established a TNF-a-promoted metastasis model, in which the ability to me...

A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer

“…It was assumed that lung metastasis was not significantly enhanced following etanercept treatment in the present study, as etanercept exhibited little effect on NK cells. This finding does not conflict with previous studies reporting that TNF blockade inhibits carcinogenesis and cancer metastasis (41,42).…”

“…Etanercept has been reported to reduce the number and size of tumors in a spontaneous colon cancer mouse model associated with chronic colitis (40). Furthermore, blockade of TNF-α has been reported to inhibit lung metastasis in a mouse model (41,42). Concerning the effect of etanercept on NK cells, etanercept was reported to inhibit the production of transforming growth factor (TGF)-β1, which subsequently led to the inhibition of NK cells and cytotoxic activity (42).…”

Blockade of transforming growth factor-β-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade

“…TAK1 has also been shown to participate in intracellular events involving the T-cell receptor, B-cell receptor, and LMP1 oncogene product of EBV (27 -29). We have recently reported that intermolecular autophosphorylation at Thr 187 is involved in the TNF-a-induced activation of TAK1 in HeLa cells (30), and the activation of TAK1 is essential for TNF-a-promoted pulmonary metastasis in murine colon carcinoma cells (31). Recently, it has been reported that suppression of the p65, JNK, and p38 signaling pathways in a kinase-inactive mutant of TAK1 increased the sensitivity of cells to apoptosis, indicating that TAK1 plays a crucial role in cell survival signaling (32).…”

Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug–Activated Gene 1 Counteracts Intestinal Ulcerative Injuries

“…This factor is thus essential for preventing injury-associated intestinal ulceration and colitis (25,26). Moreover, TAK1 is also essential for metastasis and tumor cell migration in addition to enhanced cell proliferation and survival (27). Deficiency in RhoA downstream of TAK1 suppresses tumor cell invasion and metastasis.…”