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鬼臼苦素通过不依赖胰岛素样生长因子-1受体的机制使微管解聚，从而导致有丝分裂停滞和灾难。

Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via insulin-like growth factor-1 receptor-independent mechanism.

作者信息

Waraky Ahmed, Akopyan Karen, Parrow Vendela, Strömberg Thomas, Axelson Magnus, Abrahmsén Lars, Lindqvist Arne, Larsson Olle, Aleem Eiman

机构信息

Department of Oncology-Pathology, Cancer Center Karolinska, Solna, Sweden.

Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.

出版信息

Oncotarget. 2014 Sep 30;5(18):8379-92. doi: 10.18632/oncotarget.2292.

DOI:10.18632/oncotarget.2292
PMID:25268741
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4226690/
Abstract

Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated. The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues. Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics. These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP.

摘要

小檗碱足叶草酯素（PPP）是一种正在非小细胞肺癌（NSCLC）中进行临床开发的抗癌药物。已表明PPP可抑制胰岛素样生长因子-1受体（IGF-1R）信号传导并诱导G2/M细胞周期阶段停滞，但确切机制仍有待阐明。本研究确定了PPP一种不依赖IGF-1的机制，该机制导致前中期停滞。在人癌细胞系和A549异种移植小鼠中诱导了有丝分裂阻滞，但在正常肝细胞/小鼠组织中未发生。PPP引起的细胞周期停滞在体外和体内均有发生，同时伴有显著的细胞周期蛋白依赖性激酶1（CDK1）激活，并且不依赖IGF-1R，因为在IGF-1R缺失和无效的细胞中也会发生。肿瘤细胞不是停滞在G2/M期，而是停滞在有丝分裂期。在有丝分裂进入过程中，中心体分离受到阻止，导致形成单极有丝分裂纺锤体，随后出现前中期停滞，这与Polo样激酶1（Plk1）/极光激酶A或驱动蛋白Eg5无关，并导致有丝分裂灾难的细胞特征。PPP还在数分钟内增加了可溶性微管蛋白，并减少了与纺锤体相关的微管蛋白，表明它干扰了微管动力学。这些结果提供了一种新的PPP不依赖IGF-1R的抗肿瘤作用机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/4521d1fc0e75/oncotarget-05-8379-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/c57e69be4fe4/oncotarget-05-8379-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/7f100c94ce32/oncotarget-05-8379-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/fe59ac3449b2/oncotarget-05-8379-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/4e99533ae53d/oncotarget-05-8379-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/4de40df627d8/oncotarget-05-8379-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/4521d1fc0e75/oncotarget-05-8379-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/c57e69be4fe4/oncotarget-05-8379-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/beca2375e2c6/oncotarget-05-8379-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/7f100c94ce32/oncotarget-05-8379-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/fe59ac3449b2/oncotarget-05-8379-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/4e99533ae53d/oncotarget-05-8379-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/4de40df627d8/oncotarget-05-8379-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0100/4226690/4521d1fc0e75/oncotarget-05-8379-g007.jpg

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