Mitotic entry: Non-genetic heterogeneity exposes the requirement for Plk1
Claire F Aspinall1, Daniella Zheleva2, Anthony Tighe1
1Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Abstract:
The quest to develop novel antimitotic chemotherapy agents has led to the generation of several small molecule inhibitors targeting Plk1, a protein kinase required for multiple aspects of cell division. Previous studies have shown that upon exposure to Plk1 inhibitors, cells enter mitosis, delay briefly in prophase and then arrest in mitosis due to an inability to undergo centrosome separation. Here, we show that four different classes of Plk1 inhibitor block mitotic entry in several cancer cell lines and non-transformed RPE-1 cells. The proportion of cells that arrest in G2 is cell line and concentration dependent, and is subject to non-genetic heterogeneity. Following inhibitor washout, the G2 block is alleviated and cells enter mitosis but then fail to complete cell division indicating that most Plk1 inhibitors are not fully reversible. An exception is CYC140844; in contrast to five other inhibitors examined here, this novel Plk1 inhibitor is fully reversible. We discuss the implications for developing Plk1 inhibitors as chemotherapy agents and research tools.
Insights
Novel Plk1 inhibitors show promise as chemotherapy agents by blocking cell division. However, most are not fully reversible, except for CYC140844, offering potential for research and treatment.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Polo-like kinase 1 (Plk1) is crucial for cell division.
- Plk1 inhibitors are investigated as antimitotic chemotherapy agents.
- Previous research indicated Plk1 inhibition causes mitotic arrest due to failed centrosome separation.
Purpose of the Study:
- To evaluate the effects of different Plk1 inhibitors on cell cycle progression.
- To assess the reversibility of Plk1 inhibitors after washout.
- To explore the potential of Plk1 inhibitors as chemotherapy drugs and research tools.
Main Methods:
- Treatment of cancer cell lines and RPE-1 cells with four classes of Plk1 inhibitors.
- Analysis of cell cycle distribution (G2 arrest) and mitotic progression.
- Evaluation of inhibitor reversibility upon washout.
Main Results:
- Four classes of Plk1 inhibitors blocked mitotic entry in various cell lines.
- G2 arrest was cell line and concentration-dependent, with non-genetic heterogeneity.
- Most inhibitors caused irreversible mitotic failure post-washout.
- CYC140844 demonstrated full reversibility, unlike five other inhibitors.
Conclusions:
- Plk1 inhibitors effectively block cell division but exhibit limited reversibility.
- CYC140844 represents a fully reversible Plk1 inhibitor with therapeutic and research potential.
- Understanding inhibitor reversibility is critical for developing effective Plk1-targeting cancer therapies.
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