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 ^Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.

中文翻译：

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PLK1 在 APC 截短的结肠癌细胞中具有肿瘤抑制潜力。


纺锤体组装检查点 (SAC) 作为分子保障，确保有丝分裂过程中染色体的忠实传递，有丝分裂过程受磷酸酶和激酶（包括 PLK1）之间复杂的相互作用的调节。腺瘤性结肠息肉病 (APC) 种系突变会导致非整倍性，并导致家族性腺瘤性息肉病 (FAP)。在这里，我们研究了 PLK1 在 APC 截短 (APC-ΔC) 促进染色体不稳定的结肠癌细胞中的作用。结肠细胞中 APC-ΔC 的表达减少了 PLK1 抑制后有丝分裂细胞的积累，加速有丝分裂退出并增加染色体异常增强的细胞的存活率。在有丝分裂、表达 APC-ΔC 的细胞中抑制 PLK1 会降低 Aurora B 的着丝粒水平，并阻碍 SAC 成分的募集，表明有丝分裂检查点受损。此外，Plk1 抑制（RNAi，药理学化合物）可促进两个独立的 Apc ^Min/+小鼠模型中腺瘤性息肉的发展。高 PLK1 表达可显着提高表达截短 APC 的结肠癌患者的生存率。