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CEP55 是乳腺癌有丝分裂过程中受到干扰时细胞命运的决定因素。

CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer.

机构信息

QIMR Berghofer Medical Research Institute, Herston, Qld, Australia

School of Natural Sciences, Griffith University, Nathan, Qld, Australia.

出版信息

EMBO Mol Med. 2018 Sep;10(9). doi: 10.15252/emmm.201708566.

DOI:10.15252/emmm.201708566
PMID:30108112
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6127888/
Abstract

The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase-dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2-MYC axis. Blocking MEK1/2-PLK1 signaling therefore reduced outgrowth of basal-like syngeneic and human breast tumors in models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2-PLK1 represents a potential therapeutic strategy for MYC-CEP55-dependent basal-like, triple-negative breast cancers.

摘要

中心体蛋白 CEP55 是细胞分裂的关键调节因子，其过表达与基因组不稳定性有关，这是癌症的一个标志。然而，它介导基因组不稳定性的机制尚不清楚。在这里，我们表明 CEP55 的过表达/敲低会影响非整倍体细胞的存活。CEP55 的缺失通过过早的 CDK1/周期蛋白 B 激活和 CDK1 半胱天冬酶依赖性有丝分裂细胞死亡使乳腺癌细胞对抗有丝分裂药物敏感。此外，我们表明 CEP55 是 MEK1/2-MYC 轴的下游效应物。因此，阻断 MEK1/2-PLK1 信号会减少基础样同源和人乳腺癌肿瘤在模型中的生长。总之，CEP55 水平的高低决定了有丝分裂过程中细胞的命运。通过阻断 MEK1/2-PLK1 诱导有丝分裂细胞死亡可能是治疗依赖 MYC-CEP55 的基底样三阴性乳腺癌的一种潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/089b/6127888/98e61548e018/EMMM-10-e8566-g013.jpg
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