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哌仑西平通过抑制网格蛋白激活纺锤体组装检查点并诱导分裂的 HeLa 癌细胞死亡。

Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells.

机构信息

Children's Medical Research Institute, The University of Sydney, 214 Hawkesbury Road, Westmead, NSW, 2145, Australia.

出版信息

Mol Cancer. 2013 Jan 17;12:4. doi: 10.1186/1476-4598-12-4.

DOI:10.1186/1476-4598-12-4
PMID:23327284
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3567983/
Abstract

BACKGROUND

During metaphase clathrin stabilises the mitotic spindle kinetochore (K)-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis.

RESULTS

Pitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition.

CONCLUSIONS

Pitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in dividing HeLa cells, without affecting dividing non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.

摘要

背景

在有丝分裂中期，网格蛋白稳定着有丝分裂纺锤体的动粒（K）-纤维。许多抗有丝分裂的化合物靶向微管动力学。Pitstop 2™ 是第一个网格蛋白末端结构域的小分子抑制剂，能抑制网格蛋白介导的内吞作用。我们研究了它对网格蛋白在有丝分裂中的第二个功能的影响。

结果

Pitstop 2 并没有损害网格蛋白向纺锤体的募集，但一旦固定在那里，就会破坏其功能。Pitstop 2 通过有丝分裂纺锤体完整性的丧失和纺锤体组装检查点的激活，将 HeLa 细胞困在中期，这与网格蛋白耗竭和 Aurora A 激酶抑制的表型相似。

结论

因此，Pitstop 2 是研究网格蛋白纺锤体动力学的新工具。Pitstop 2 降低了分裂的 HeLa 细胞的活力，而不影响分裂的非癌细胞系 NIH3T3 细胞，这表明网格蛋白可能是一种新的抗有丝分裂药物靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34ab/3567983/cc46a26e4cbe/1476-4598-12-4-7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/34ab/3567983/4d5173d65e1c/1476-4598-12-4-1.jpg
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