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Plk1 overexpression suppresses tumor development by inducing chromosomal instability

Guillermo de Cárcer, Sharavan Vishaan Venkateswaran, Lorena Salgueiro, Aicha El Bakkali, Kalman Somogyi, Konstantina Rowald, Pablo Montañes, Manuel Sanclemente, Beatriz Escobar, Alba de Martino, Nicholas McGranahan, Marcos Malumbres, Rocío Sotillo
doi: https://doi.org/10.1101/285635
Guillermo de Cárcer
1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029 Madrid, Spain
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  • For correspondence: gcarcer@cnio.es malumbres@cnio.es r.sotillo@dkfz-heidelberg.de
Sharavan Vishaan Venkateswaran
2Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3Faculty of Biosciences, Heidelberg University, Germany
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Lorena Salgueiro
2Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Aicha El Bakkali
1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029 Madrid, Spain
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Kalman Somogyi
2Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Konstantina Rowald
2Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Pablo Montañes
1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029 Madrid, Spain
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Manuel Sanclemente
1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029 Madrid, Spain
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Beatriz Escobar
1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029 Madrid, Spain
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Alba de Martino
4Histopathology Unit, Spanish National Cancer Research Centre (CNIO)
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Nicholas McGranahan
5Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London WC1E 6BT, UK
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Marcos Malumbres
1Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029 Madrid, Spain
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  • For correspondence: gcarcer@cnio.es malumbres@cnio.es r.sotillo@dkfz-heidelberg.de
Rocío Sotillo
2Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
6Translational Lung Research Center Heidelberg (TRLC), German Center for Lung Research (DZL)
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  • For correspondence: gcarcer@cnio.es malumbres@cnio.es r.sotillo@dkfz-heidelberg.de
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Abstract

Polo-like kinase 1 (Plk1) is a protein kinase currently considered as an attractive cancer target due to its critical role in the cell division cycle. Plk1 is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression does not favor cell proliferation but rather results in abnormal chromosome segregation and cytokinesis, leading to the formation of polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge during cytokinesis in a Plk1 kinase-dependent manner. In vivo, elevated levels of Plk1 markedly prevent the development of mammary gland tumors induced either by KrasG12D or Her2, in the presence of increased rates of chromosome instability. In patients, higher Plk1 expression levels are associated with significantly increased overall survival in breast cancer subtypes. These data suggest that, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor suppressive properties by perturbing mitotic progression and cytokinesis.

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Posted March 20, 2018.
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Plk1 overexpression suppresses tumor development by inducing chromosomal instability
Guillermo de Cárcer, Sharavan Vishaan Venkateswaran, Lorena Salgueiro, Aicha El Bakkali, Kalman Somogyi, Konstantina Rowald, Pablo Montañes, Manuel Sanclemente, Beatriz Escobar, Alba de Martino, Nicholas McGranahan, Marcos Malumbres, Rocío Sotillo
bioRxiv 285635; doi: https://doi.org/10.1101/285635
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Plk1 overexpression suppresses tumor development by inducing chromosomal instability
Guillermo de Cárcer, Sharavan Vishaan Venkateswaran, Lorena Salgueiro, Aicha El Bakkali, Kalman Somogyi, Konstantina Rowald, Pablo Montañes, Manuel Sanclemente, Beatriz Escobar, Alba de Martino, Nicholas McGranahan, Marcos Malumbres, Rocío Sotillo
bioRxiv 285635; doi: https://doi.org/10.1101/285635

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