Meng Fandong, Li Yan, Tian Xin, Fu Liye, Yin Yuanqin, Sui Chengguang, Ma Ping, Jiang Youhong
Molecular Oncology Department of Cancer Research Institution, The First Hospital of China Medical University, Shengyang, Liaoning City 110001, China.
Molecular Oncology Department of Cancer Research Institution, The First Hospital of China Medical University, Shengyang, Liaoning City 110001, China.
Biochem Biophys Res Commun. 2014 Oct 10;453(1):106-11. doi: 10.1016/j.bbrc.2014.09.070. Epub 2014 Sep 26.
Renal cell carcinoma (RCC) is common renal malignancy within poor prognosis. TGF-β-activated kinase 1 (TAK1) plays vital roles in cell survival, apoptosis-resistance and carcinogenesis through regulating nuclear factor-κB (NF-κB) and other cancer-related pathways. Here we found that TAK1 inhibitors (LYTAK1, 5Z-7-oxozeanol (5Z) and NG-25) suppressed NF-κB activation and RCC cell (786-O and A489 lines) survival. TAK1 inhibitors induced apoptotic cytotoxicity against RCC cells, which was largely inhibited by the broad or specific caspase inhibitors. Further, shRNA-mediated partial depletion of TAK1 reduced 786-O cell viability whiling activating apoptosis. Significantly, TAK1 was over-expressed in human RCC tissues, and its level was correlated with phosphorylated NF-κB. Finally, kinase inhibition or genetic depletion of TAK1 enhanced the activity of vinblastine sulfate (VLB) in RCC cells. Together, these results suggest that TAK1 may be an important oncogene or an effective target for RCC intervention.
肾细胞癌（RCC）是一种预后较差的常见肾脏恶性肿瘤。转化生长因子-β激活激酶1（TAK1）通过调节核因子-κB（NF-κB）及其他与癌症相关的信号通路，在细胞存活、抗凋亡和致癌过程中发挥着至关重要的作用。在此，我们发现TAK1抑制剂（LYTAK1、5Z-7-氧代泽醇（5Z）和NG-25）可抑制NF-κB的激活以及肾癌细胞（786-O和A489细胞系）的存活。TAK1抑制剂可诱导肾癌细胞发生凋亡性细胞毒性，而这种毒性在很大程度上被广谱或特异性半胱天冬酶抑制剂所抑制。此外，shRNA介导的TAK1部分缺失可降低786-O细胞的活力，同时激活细胞凋亡。值得注意的是，TAK1在人肾癌细胞组织中过度表达，其水平与磷酸化的NF-κB相关。最后，TAK1的激酶抑制或基因缺失可增强硫酸长春碱（VLB）在肾癌细胞中的活性。综上所述，这些结果表明TAK1可能是一种重要的癌基因或肾细胞癌干预的有效靶点。
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