Molecular mechanism of metastasis promoting activity of stress response kinase TAK1

我们分析了应激反应激酶TAK1在肿瘤进展中的作用。TRAIL是一种选择性诱导肿瘤细胞凋亡的细胞因子，在TRAIL信号转导通路中起着关键作用，它调控着JNK、p38MAPKs以及IKK-NF-κB通路。用化学抑制剂或siRNA阻断TRAIL诱导的TAK1活化可促进癌细胞的凋亡，但不能促进小鼠胚胎成纤维细胞的凋亡。这些结果表明，在临床肿瘤治疗中，TAK1是增强TRAIL诱导的细胞凋亡的一个有趣的靶点。我们还发现，肿瘤坏死因子-α一过性地抑制了表皮生长因子受体的功能。P38-TAK1介导的EGFR磷酸化参与了这种抑制作用。这种磷酸化通过网状蛋白介导的机制导致EGFR的快速内化。EGFR在10分钟内内化，但在60分钟内通过去磷酸化循环到细胞表面。转移是肿瘤进展的主要原因之一。为了探讨Tak1在肿瘤坏死因子-α促进肿瘤转移中的作用，我们利用结肠腺癌细胞建立了肿瘤坏死因子-α体外刺激模型。体外用肿瘤坏死因子-α处理的细胞促进了向肺转移的能力。我们发现Tak1通过激活下游的jnk和p38参与了肿瘤坏死因子-α诱导的肿瘤转移的促进。综上所述，这些发现为开发治疗肿瘤进展，特别是转移的新的治疗策略提供了信息。

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.