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Abstract：
TNKS is a new target for the treatment of lung adenocarcinoma, the synergistic effects of the TCM compound Xiaoyan decoction and the TNKS inhibitor E7449 in the intervention on TNKS were investigated, and the possible underlying mechanisms involved were clarified. Immunohistochemistry was used to analyse TNKS expression in tumour tissues. The impact of targeting TNKS on cell growth, invasion, apoptosis, key genes and signalling pathways was investigated in tumour cells by Western blotting, rescue experiments, colony formation assays, flow cytometry and label-free experiments. Tumour xenografts with A549 cells were then transplanted for in vivo study. We found that TNKS high expression was closely related to the advanced tumour stage and tumour size in lung adenocarcinom. After TNKS was knocked down in vitro, the growth, proliferation, migration and invasion were markedly reduced in A549 and H1975 cells. We subsequently applied the Xiaoyan decoction and TNKS inhibitors to intervene in lung adenocarcinoma. Xiaoyan decoction and E7449 suppressed TNKS expression and inhibited adenocarcinoma cell proliferation, migration, invasion and apoptosis in vitro. Proteomic analysis revealed that E7449 treatment may be most closely associated with the classic Wnt/β-catenin pathway, whereas Xiaoyan decoction treatment may be related to the WNT/PLAN pathway. Xenograft studies confirmed that E7449 or Xiaoyan decoction inhibited lung tumour growth in vivo and attenuated the Wnt signalling pathway in adenocarcinoma. These findings suggest that TNKS is a novel therapeutic target. TCM preparations and small molecule inhibitors are expected to constitute an effective combination strategy.
摘要：
TNKS是治疗肺腺癌的新靶点,研究中药复方消炎汤与TNKS抑制剂E7449在干预TNKS中的协同作用,并阐明了可能涉及的潜在机制。免疫组织化学用于分析肿瘤组织中的TNKS表达。靶向TNKS对细胞生长的影响，入侵,凋亡，通过蛋白质印迹在肿瘤细胞中研究了关键基因和信号通路，救援实验,集落形成试验,流式细胞术和无标记实验。然后移植具有A549细胞的肿瘤异种移植物用于体内研究。我们发现TNKS的高表达与肺腺癌的晚期肿瘤分期和肿瘤大小密切相关。TNKS在体外被击倒后，增长,扩散,A549和H1975细胞的迁移和侵袭能力显著降低。随后，我们应用消炎汤和TNKS抑制剂干预肺腺癌。消炎汤和E7449抑制TNKS表达，抑制腺癌细胞增殖，迁移,体外侵袭和凋亡。蛋白质组学分析显示，E7449治疗可能与经典的Wnt/β-catenin通路密切相关。而消炎汤治疗可能与WNT/PLAN通路有关。异种移植研究证实E7449或消炎汤在体内抑制肺肿瘤生长并减弱腺癌中的Wnt信号通路。这些发现表明TNKS是一种新的治疗靶标。中药制剂与小分子抑制剂有望构成有效的组合策略。
