Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways
Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways
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DOI：
10.1158/1535-7163.mct-13-0918
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发表时间：
2014-06-01
影响因子：
5.7
通讯作者：
Rebbaa, Abdelhadi
中科院分区：
文献类型：
--
作者：
Basu, Dipanjan;Lettan, Robert;Rebbaa, Abdelhadi
胚胎信号通路，尤其是由Wnt和转化生长因子-β介导的信号通路，通过诱导上皮-间充质转化(EMT)在肿瘤进展中发挥关键作用。因此，它们的同时靶向可能代表着一种理想的抗癌策略。根据最近的发现，在哺乳动物细胞中，Wnt和TGF-β相关的通路都受到Hippo信号的调控，我们推测，针对后者将更有效地抑制EMT。在寻找这种抑制剂的过程中，我们发现了一个小分子(C19)，它不仅对河马具有显著的抑制活性，而且对Wnt和转化生长因子-β途径也具有显著的抑制活性。C19在体外抑制癌细胞的迁移、增殖和对阿霉素的耐药性，并在小鼠肿瘤模型中发挥强大的抗肿瘤活性。在机制上，C19通过激活河马蛋白激酶MST/LATS和降解复合体上游的肿瘤抑制激酶AMPK，诱导GSK3-β介导的河马转导蛋白TAZ的降解。总体而言，本研究确定C19是一种具有独特作用机制的多EMT途径抑制物。AMPK和MST/LATS都介导了C19的抗肿瘤活性，这一发现揭示了代谢和器官大小控制途径之间在调节癌症进展方面的潜在串扰。通过同时靶向这两条途径，C19可能代表着一种新型的抑制癌症进展和/或其复发的药物。(C)2014年AACR。
Embryonic signaling pathways, in particular those mediated by Wnt and TGF-beta, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-beta-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-beta pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-beta-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence. (C) 2014 AACR.