Zhou Jundong, Zheng Bing, Ji Jiansong, Shen Fei, Min Han, Liu Biao, Wu Jinchang, Zhang Shuyu
The Core Laboratory of the Suzhou Cancer Center and Department of Radiotherapy, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, China.
Tumour Biol. 2015 May;36(5):3301-8. doi: 10.1007/s13277-014-2961-2. Epub 2014 Dec 19.
KRAS mutation in colorectal cancer (CRC) activates transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) to promote tumor progression. In the current study, we explored the potential effect of LYTAK1, a novel TAK1 inhibitor, against KRAS mutant CRC cells in vitro and in vivo. We found that LYTAK1 dose-dependently inhibited KRAS mutant CRC cell (HT-29 and SW-620 lines) growth, and induced cell cycle G1-S arrest. Further, LYTAK1 activated apoptosis in HT-29 cells and SW-620 cells, and apoptosis inhibitors almost reversed LYTAK1-mediated growth inhibition. While in KRAS wild-type (WT) CRC cell lines (DLD-1 and HCT-116), LYTAK1 had almost no effect on cell growth, cell cycle progression, or cell apoptosis. In KRAS mutant HT-29 cells and SW-260 cells, LYTAK1 blocked TAK1 activation or phosphorylation at Thr-184/187. Activation of nuclear factor κB (NF-κB) in these cells, detected by phosphorylations of p65 and IκB kinase α (IKKα) as well as expression of NF-κB-regulated gene cyclin D1, was significantly inhibited by LYTAK1. Further, LYTAK1 treatment resulted in downregulation of β-catenin and Wnt response gene Axin 2, indicating Wnt inactivation. In vivo, oral LYTAK1 significantly inhibited HT-29 xenograft growth in nude mice. Together, these results show that LYTAK1 inhibits KRAS mutant CRC cell growth both in vitro and in vivo. LYTAK1 might be investigated as a novel agent against CRC with KRAS mutation.
结直肠癌（CRC）中的KRAS突变激活转化生长因子-β（TGF-β）激活激酶1（TAK1）以促进肿瘤进展。在本研究中，我们探讨了新型TAK1抑制剂LYTAK1在体外和体内对KRAS突变型CRC细胞的潜在作用。我们发现LYTAK1剂量依赖性地抑制KRAS突变型CRC细胞（HT-29和SW-620细胞系）的生长，并诱导细胞周期G1-S期阻滞。此外，LYTAK1激活HT-29细胞和SW-620细胞中的凋亡，凋亡抑制剂几乎逆转了LYTAK1介导的生长抑制。而在KRAS野生型（WT）CRC细胞系（DLD-1和HCT-116）中，LYTAK1对细胞生长、细胞周期进程或细胞凋亡几乎没有影响。在KRAS突变型HT-29细胞和SW-260细胞中，LYTAK1阻断TAK1在苏氨酸184/187位点的激活或磷酸化。通过p65和IκB激酶α（IKKα）的磷酸化以及NF-κB调节基因细胞周期蛋白D1的表达检测到的这些细胞中核因子κB（NF-κB）的激活被LYTAK1显著抑制。此外，LYTAK1处理导致β-连环蛋白和Wnt反应基因Axin 2的下调，表明Wnt失活。在体内，口服LYTAK1显著抑制裸鼠中HT-29异种移植瘤的生长。总之，这些结果表明LYTAK1在体外和体内均抑制KRAS突变型CRC细胞的生长。LYTAK1可能作为一种针对KRAS突变型CRC的新型药物进行研究。
