Lung cancer is the most frequent cancer worldwide with a poor prognosis. Identification of novel cancer targets and useful therapeutic strategies without toxicity are urgently needed. In this study, we screened natural products for anticancer bioactivity in a library consisting of 429 small molecules. We demonstrated for the first time that daurisoline, a constituent of Rhizoma Menispermi, repressed lung cancer cell proliferation by inducing cell cycle arrest at the G1 phase. Furthermore, daurisoline was found not only to suppress the growth of lung tumor xenografts in animals without obvious side effects, but also to inhibit cell migration and invasion. Mechanistically, quantitative proteomics and bioinformatics analyses, Western blotting and qRT-PCR confirmed that daurisoline exerted its anticancer effects by inhibiting the expression levels of β-catenin and its downstream targets c-myc and cyclin D1. Furthermore, our data from Drug Affinity Responsive Target Stability (DARTS), isothermal titration calorimetry (ITC) and a series of functional assays demonstrated that daurisoline could target HSP90 directly and disrupt its interaction with β-catenin, therefore increasing the ubiquitin-mediated proteasomal degradation of β-catenin. This study reveals that daurisoline could be a promising therapeutic strategy for the treatment of lung cancer.

肺癌是全世界最常见的预后不良的癌症。迫切需要鉴定新的癌症靶标和无毒性的有用治疗策略。在这项研究中，我们在一个包含429个小分子的文库中筛选了天然产物的抗癌生物活性。我们首次证明了半乳糖根黄酮（半根茎的成分）通过诱导G1期细胞周期停滞，抑制了肺癌细胞的增殖。此外，发现daurisoline不仅可以抑制动物的肺肿瘤异种移植物的生长而没有明显的副作用，而且还可以抑制细胞的迁移和侵袭。从机理上进行定量蛋白质组学和生物信息学分析，Western印迹和qRT-PCR证实daurisoline通过抑制β-catenin及其下游靶标c-myc和cyclin D1的表达水平发挥其抗癌作用。此外，我们从药物亲和响应靶标稳定性（DARTS），等温滴定量热法（ITC）和一系列功能分析得出的数据表明，daurisoline可以直接靶向HSP90并破坏其与β-catenin的相互作用，因此增加了泛素介导的蛋白酶体降解β-catenin。