Pyrenocine A induces monopolar spindle formation and suppresses proliferation of cancer cells
Pyrenocine A induces monopolar spindle formation and suppresses proliferation of cancer cells
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DOI：
10.1016/j.bmc.2019.115149
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发表时间：
2019-12-01
影响因子：
3.5
通讯作者：
Sugawara, Fumio
中科院分区：
文献类型：
--
作者：
Myobatake, Yusuke;Kamisuki, Shinji;Sugawara, Fumio
Pyrenocine A是一种植物毒素，对癌细胞具有细胞毒性，IC50值为2.6 ~ 12.9 μ M.活细胞成像分析显示，Pyrenocine A在具有特征环状染色体的M期阻滞HeLa细胞。此外，通过免疫荧光染色分析，我们发现pyrenocine a导致HeLa细胞形成单极纺锤体。单极纺锤体是由运动蛋白Eg5的抑制剂如monastrol和STLC诱导的。Monastrol和STLC通过抑制Eg5的atp酶活性诱导单极纺锤体形成和M相阻滞。有趣的是，我们的数据显示，pyrenocine A对体外Eg5的atp酶活性没有影响，这表明该化合物通过一种未知的机制诱导单极纺锤体。构效关系分析表明，芘A的烯酮结构可能与其细胞毒性有关。我们合成了一种炔标记的pyrenocine A类似物，其抑制HeLa细胞的增殖，IC50值为2.3 μ m。我们得出pyrenocine A诱导单极纺锤体形成的新机制不是直接抑制Eg5运动活性，而pyrenocine A的活性可能提示了一种新的抗癌机制。
Pyrenocine A, a phytotoxin, was found to exhibit cytotoxicity against cancer cells with an IC50 value of 2.6-12.9 mu M. Live cell imaging analysis revealed that pyrenocine A arrested HeLa cells at the M phase with characteristic ring-shaped chromosomes. Furthermore, as a result of immunofluorescence staining analysis, we found that pyrenocine A resulted in the formation of monopolar spindles in HeLa cells. Monopolar spindles are known to be induced by inhibitors of the kinesin motor protein Eg5 such as monastrol and STLC. Monastrol and STLC induce monopolar spindle formation and M phase arrest via inhibition of the ATPase activity of Eg5. Interestingly, our data revealed that pyrenocine A had no effect on the ATPase activity of Eg5 in vitro, which suggested the compound induces a monopolar spindle by an unknown mechanism. Structure-activity relationship analysis indicates that the enone structure of pyrenocine A is likely to be important for its cytotoxicity. An alkyne-tagged analog of pyrenocine A was synthesized and suppressed proliferation of HeLa cells with an IC50 value of 2.3 mu M. We concluded that pyrenocine A induced monopolar spindle formation by a novel mechanism other than direct inhibition of Eg5 motor activity, and the activity of pyrenocine A may suggest a new anticancer mechanism.