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Molecular mechanism of metastasis promoting activity of stress response kinase TAK1

应激反应激酶TAK1促进转移活性的分子机制

基本信息

批准号：
17590055
负责人：
SAKURAI Hiroaki
金额：
$ 2.37万
依托单位：
University of Toyama
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590055/
关键词：
TAK1 TRAIL TNF-α apoptosis NF-κB MAPK がん転移 IL-2 T細胞

项目摘要

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.

我们分析了应激反应激酶TAK 1在肿瘤进展中的作用。TAK 1在选择性诱导肿瘤细胞凋亡的细胞因子TRAIL信号通路中起关键作用，其中TAK 1调节JNK、p38 MAPK以及IKK-NF-κB通路。通过化学抑制剂或siRNA阻断TRAIL诱导的TAK 1活化导致癌细胞的凋亡增强，但不导致小鼠胚胎成纤维细胞的凋亡。这些结果表明，TAK 1是一个有趣的目标，以提高TRAIL诱导的细胞凋亡在临床癌症治疗。我们还发现TNF-α可瞬时抑制EGFR的受体功能。p38-TAK 1介导的EGFR磷酸化参与了这种抑制。磷酸化通过网格蛋白介导的机制导致EGFR的快速内化。EGFR在10 min内发生内化，60 min后通过脱磷酸化作用聚集到细胞表面，转移是肿瘤进展的主要原因之一。为了研究TAK 1在TNF-α促进肿瘤转移中的作用，我们建立了体外TNF-α刺激结肠26腺癌细胞模型。体外用TNF-α处理的细胞具有促进向肺转移的能力。我们发现TAK 1通过激活下游激酶JNK和p38参与了TNF-α诱导的肿瘤转移过程，这些发现为肿瘤进展尤其是转移的治疗提供了新的思路。