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PLK1 在 APC 截断的结肠癌细胞中具有肿瘤抑制潜能。

PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells.

机构信息

Department of Gynecology, Goethe-University, 60590, Frankfurt, Germany.

German Cancer Consortium (DKTK)/ German Cancer Research Center, 69120, Heidelberg, Germany.

出版信息

Nat Commun. 2018 Mar 16;9(1):1106. doi: 10.1038/s41467-018-03494-4.

DOI:10.1038/s41467-018-03494-4
PMID:29549256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5856809/
Abstract

The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.

摘要

纺锤体组装检查点（SAC）作为一种分子保障，在有丝分裂过程中确保染色体的忠实传递，这是由包括 PLK1 在内的磷酸酶和激酶之间的复杂相互作用调控的。腺瘤性结肠息肉病（APC）种系突变导致非整倍体，是家族性腺瘤性息肉病（FAP）的原因。在这里，我们研究了在 APC 截断（APC-ΔC）促进的染色体不稳定的结肠癌细胞中 PLK1 的作用。APC-ΔC 在结肠细胞中的表达减少了 PLK1 抑制后有丝分裂细胞的积累，加速了有丝分裂退出，并增加了染色体异常增强细胞的存活率。在 APC-∆C 表达细胞的有丝分裂中抑制 PLK1 会降低着丝粒水平的 Aurora B，并阻碍 SAC 成分的募集，表明有丝分裂检查点受损。此外，在两个独立的 Apc 小鼠模型中，Plk1 抑制（RNAi、药理学化合物）促进了腺瘤的发展。高 PLK1 表达显著增加了表达截断 APC 的结肠癌患者的存活率。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/56e22379398b/41467_2018_3494_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/133cabfa810b/41467_2018_3494_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/52e8ca6aa6fe/41467_2018_3494_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/5d838ab8f8a4/41467_2018_3494_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/02e39cc89461/41467_2018_3494_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/351506b9a61d/41467_2018_3494_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/f4d14fbc45b6/41467_2018_3494_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/28efa18421d6/41467_2018_3494_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/e5edd74aa5a9/41467_2018_3494_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/56e22379398b/41467_2018_3494_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/133cabfa810b/41467_2018_3494_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/52e8ca6aa6fe/41467_2018_3494_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/5d838ab8f8a4/41467_2018_3494_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/02e39cc89461/41467_2018_3494_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/351506b9a61d/41467_2018_3494_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/f4d14fbc45b6/41467_2018_3494_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/28efa18421d6/41467_2018_3494_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/e5edd74aa5a9/41467_2018_3494_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/79d8/5856809/56e22379398b/41467_2018_3494_Fig9_HTML.jpg

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