Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, China.
Chem Biol Interact. 2018 Oct 1;294:18-27. doi: 10.1016/j.cbi.2018.08.010. Epub 2018 Aug 17.
Non-small cell lung cancer (NSCLC) is known as highly metastatic disease because it is difficult to diagnose at early stage. More than 60% of NSCLC patients' overexpress receptor tyrosine kinase (RTK) such as EGFR that has been proved to display resistance to receptor tyrosine kinase inhibitor (TKI) through PI3K signaling, while single PI3K inhibitors increase RTK expression as feedback. So, to select the proper targeted agent or target an assortment of molecular subsets, such as EGFR mutations for different subgroups of patients with NSCLC is urgent. Compound BENC-511, a potent PI3K inhibitor, had effects on inhibiting cancer cell survival and delaying tumor growth, but the effects and mechanisms on cancer metastasis are not clear. Methods of Scratch assay, Transwell system, experimental metastasis mice models, plasmid transfection, quantitative real-time PCR and Western blot were used. Results showed that BENC-511 could significantly inhibit lung cancer cells invasion and metastasis both in vitro and in vivo. And it not only inhibited PI3K/Akt signal pathway, but also directly suppressed phosphorylation of EGFR and nuclear translocation of β-catenin. Moreover, our study firstly reported BENC-511 seemed more sensitive to NSCLC cells that highly expressed Zinc-finger E-box binding protein 1 (ZEB1), one of the epithelial-mesenchymal transition (EMT) inducer, and knockdown of ZEB1 could improve the effects of this compound. These findings suggested that BENC-511 should be a promising lead molecule for anti-metastasis therapy by targeting β-catenin/ZEB1 regulatory loop and serve as a therapeutic agent to inhibit metastasis of NSCLC.
非小细胞肺癌（NSCLC）是一种高度转移性疾病，因为它很难在早期被诊断出来。超过 60%的 NSCLC 患者过度表达受体酪氨酸激酶（RTK），如 EGFR，已经证明其通过 PI3K 信号对受体酪氨酸激酶抑制剂（TKI）显示出耐药性，而单一的 PI3K 抑制剂会增加 RTK 的表达作为反馈。因此，选择适当的靶向药物或针对 EGFR 突变等不同亚组的分子亚群，对于不同的 NSCLC 患者是紧迫的。BENC-511 是一种有效的 PI3K 抑制剂，它可以抑制癌细胞的存活并延缓肿瘤的生长，但它对癌症转移的作用和机制尚不清楚。我们采用划痕实验、Transwell 系统、实验性转移小鼠模型、质粒转染、实时定量 PCR 和 Western blot 等方法。结果表明，BENC-511 可显著抑制体外和体内肺癌细胞的侵袭和转移。它不仅抑制了 PI3K/Akt 信号通路，而且直接抑制了 EGFR 的磷酸化和β-catenin 的核转位。此外，我们的研究首次报道 BENC-511 似乎对高表达锌指 E 盒结合蛋白 1（ZEB1）的 NSCLC 细胞更敏感，ZEB1 是上皮-间充质转化（EMT）诱导剂之一，敲低 ZEB1 可以提高该化合物的作用。这些发现表明，BENC-511 可能是一种有前途的针对β-catenin/ZEB1 调节环的抗转移治疗的先导分子，并可作为抑制 NSCLC 转移的治疗剂。
