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 ApcMin/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.
Highlights
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 Polo-like kinase 1 (PLK1)
Chromosomal instability (CIN) represents the most frequent form of genomic instability, which correlates to a high rate by which chromosome structure and number changes over time in cancer cells compared to normal cells.In hereditary types of cancer characterized by the presence of CIN, mutations in DNA repair genes have been correlated to genomic instability
To investigate the role of PLK1 in cancer cells with CIN, we expressed in both cell lines a truncated Adenomatous polyposis coli (APC) protein containing amino acids 1-750 of APC, hereafter named APC-ΔC, removing all β-Catenin regulatory sequences (Fig. 1a, b, upper left panels)
Summary
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. We study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). It plays key roles for centrosome maturation[13], Golgi fragmentation[14], spindle assembly and function[15,16], kinetochore function[17,18], centromere assembly[19] and cytokinesis[20] It promotes DNA replication[21], mitotic entry[22], removal of sister chromatid cohesion[23], chromosome condensation[24] and APC/C activity[25]. PLK1 is expressed at higher levels in tumors compared to paired normal mucosa from the same patient in several independent studies[28,29], and the degree of overexpression correlates with adverse prognosis[30].
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