A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers
A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers
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DOI：
10.1073/pnas.1716009114
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发表时间：
2017-11-14
影响因子：
11.1
通讯作者：
Lairson, Luke L.
中科院分区：
文献类型：
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作者：
Bollong, Michael J.;Pietila, Mika;Lairson, Luke L.
转录因子FOXC 2的表达是诱导的，并且是成功的上皮-间充质转化所必需的，上皮-间充质转化是一种发育程序，当在癌症中被激活时，赋予细胞转移潜能和干细胞的特性。因此，鉴定抑制FOXC 2转化细胞生长的药物代表了抑制化疗耐药性和转移性播散的有吸引力的方法。从高通量合成致死筛选中，我们确定了一种小分子FiVe 1，它选择性地和不可逆地抑制不同组织学亚型的间充质转化乳腺癌细胞和软组织肉瘤的生长。FiVe 1靶向中间丝和间充质标志物波形蛋白（Vim）的模式，促进Vim解体和磷酸化中期，最终导致有丝分裂灾难，多核化，和干性的损失。这些发现阐明了一种以前未描述的中断忠实有丝分裂进展的机制，并可能最终为广泛的间充质癌的治疗设计提供信息。
Expression of the transcription factor FOXC2 is induced and necessary for successful epithelial-mesenchymal transition, a developmental program that when activated in cancer endows cells with metastatic potential and the properties of stem cells. As such, identifying agents that inhibit the growth of FOXC2-transformed cells represents an attractive approach to inhibit chemotherapy resistance and metastatic dissemination. From a high throughput synthetic lethal screen, we identified a small molecule, FiVe1, which selectively and irreversibly inhibits the growth of mesenchymally transformed breast cancer cells and soft tissue sarcomas of diverse histological subtypes. FiVe1 targets the intermediate filament and mesenchymal marker vimentin (VIM) in a mode which promotes VIM disorganization and phosphorylation during metaphase, ultimately leading to mitotic catastrophe, multinucleation, and the loss of stemness. These findings illustrate a previously undescribed mechanism for interrupting faithful mitotic progression and may ultimately inform the design of therapies for a broad range of mesenchymal cancers.