Direct targeting of HSP90 with daurisoline destabilizes β-catenin to suppress lung cancer tumorigenesis
Direct targeting of HSP90 with daurisoline destabilizes β-catenin to suppress lung cancer tumorigenesis
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Daurisoline 直接靶向 HSP90 可破坏 β-catenin 的稳定性，从而抑制肺癌肿瘤发生
DOI：
10.1016/j.canlet.2020.05.024
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发表时间：
2020-10-01
期刊：
影响因子：
9.7
通讯作者：
He, Qing-Yu
中科院分区：
文献类型：
--
作者：
Huang, Xiao-Hui;Yan, Xin;He, Qing-Yu
肺癌是世界上最常见的癌症，预后不良。目前迫切需要找到新的肿瘤靶点和有效的无毒性治疗策略。在这项研究中，我们筛选天然产物的抗癌生物活性的库组成的429个小分子。我们首次证明北豆根的成分蝙蝠葛苏林碱通过诱导细胞周期停滞在G1期来抑制肺癌细胞增殖。此外，发现蝙蝠葛苏林不仅可以抑制动物肺肿瘤异种移植物的生长，且无明显副作用，还可以抑制细胞迁移和侵袭。定量蛋白质组学和生物信息学分析、Western blotting和qRT-PCR证实蝙蝠葛苏林碱通过抑制β-catenin及其下游靶点c-myc和cyclin D1的表达水平发挥其抗癌作用。此外，我们的药物亲和反应靶点稳定性（DARTS），等温滴定量热法（ITC）和一系列功能试验的数据表明，蝙蝠葛苏林可以直接靶向HSP 90，并破坏其与β-catenin的相互作用，从而增加泛素介导的β-catenin的蛋白酶体降解。本研究显示蝙蝠葛苏林碱可能是一种有前途的治疗肺癌的策略。
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 beta-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 beta-catenin, therefore increasing the ubiquitin-mediated proteasomal degradation of beta-catenin. This study reveals that daurisoline could be a promising therapeutic strategy for the treatment of lung cancer.