2006 Fiscal Year Final Research Report Summary
Molecular mechanism of metastasis promoting activity of stress response kinase TAK1
| Project/Area Number |
17590055
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | University of Toyama |
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Principal Investigator |
SAKURAI Hiroaki University of Toyama, Institute of Natural Medicine, Associate Professor, 和漢医薬学総合研究所, 助教授 (00345571)
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| Co-Investigator(Kenkyū-buntansha) |
SAIKI Ikuo University of Toyama, Institute of Natural Medicine, Professor, 和漢医薬学総合研究所, 教授 (80133776)
KOIZUMI Keiichi University of Toyama, Institute of Natural Medicine, Assistant Professor, 和漢医薬学総合研究所, 助手 (10334715)
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| Project Period (FY) |
2005 – 2006
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| Keywords | TAK1 / TRAIL / TNF-α / apoptosis / NF-κB / MAPK |
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| Research Abstract |
We have analyzed role of stress response kinase TAK1 in tumor progression. TAK1 plays a key role in TRAIL, a cytokine that selectively induces apoptosis of cancer cells, signaling pathway, in which TAK1 regulates JNK, p38 MAPKs as well as IKK-NF-κB pathway. Blockade of TRAIL-induced activation of TAK1 by chemical inhibitor or siRNA resulted in enhance apoptosis of cancer cells, but not murine embryonic fibroblast. These results suggest that TAK1 is an interesting target to enhance TRAIL-induced apoptosis in clinical cancer therapy. We have also found that TNF-α transiently suppresses the receptor function of EGFR. The p38-TAK1-mediated phosphorylation of EGFR is involved in this suppression. The phosphorylation leads to rapid internalization of EGFR through a Clathrin-mediated mechanism. Internalization of EGFR is occurred within 10 min ; however, it recycles to the cell surface at 60 min by dephosphorylation.
Metastasis is one of the major causes of tumor progression. To investigate the role of TAK1 in TNF-α-promoted tumor metastasis, we developed in vitro TNF-α stimulation model using colon 26 adenocarcinoma cells. Cells treated with TNF-α in vitro have promoted ability to metastasize to the lung. We found that TAK1 is involved in TNF-α-induced promotion of metastasis though activation of the downstream kinases JNK and p38.
In summary, these findings provide information to develop a novel therapeutic strategy for the treatment of tumor progression, especially metastasis.
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Research Products
(44 results)
