Abstract

Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II–dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II–treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.

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Acknowledgements

We are fully indebted to K. Burridge (The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA), C.J. Der (The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA), A.P. Fields (Mayo Clinic, Jacksonville, Florida, USA), M. Glotzer (University of Chicago, Chicago, Illinois, USA), M. Angel del Pozo (CNIC, Madrid, Spain) and M. Yaffe (The Koch Institute, MIT, Cambridge, Massachusetts, USA) for reagents. We thank A. Borgia for help with biochemical studies; the ultrasonographers A.V. Alonso and L. Flores; A. Peral and R. Alberca for technical assistance; J. Regadera for advice on mouse echocardiography and pathological samples; and members of the Histopathology and Transgenic Units of the CNIO for excellent technical support. We also thank D. Olmos for discussion on the effect of Plk1 inhibitors in the clinic. This work was supported by the Marie Curie activities of the European Commission (Oncotrain program; fellowship to P.W.), the Spanish Ministry of Economy and Competitiveness (MINECO; fellowship to A.G.-L.), the CENIT AMIT Project “Advanced Molecular Imaging Technologies” (TEC2008-06715-C02-1, RD07/0014/2009 to F.M.), the Red de Investigación Cardiovascular (RIC), cofunded by FEDER (grant RD12/0042/0022 to J.M.R.; grant RD12/0042/0056 to L.J.J.-B.), Fundació La Marató TV3 (grant 20151331 to J.M.R.), the Castilla-León Autonomous Government (BIO/SA01/15, CS049U16 to X.R.B.), the Solórzano and Ramón Areces Foundations (to X.R.B.), MINECO (grants RD12/0036/0002 and SAF2015-64556-R to X.R.B.; SAF2015-63633-R to J.M.R.; and SAF2015-69920-R to M.M.), Consolider-Ingenio 2010 Programme (grant SAF2014-57791-REDC to M.M.), Red Temática CellSYS (grant BFU2014-52125-REDT to M.M.), Comunidad de Madrid (OncoCycle Programme; grant S2010/BMD-2470 to M.M.), Worldwide Cancer Research (grants 14-1248 to X.R.B., and 15-0278 to M.M.) and the MitoSys project (European Union Seventh Framework Programme; grant HEALTH-F5-2010-241548 to M.M.). CNIC is supported by MINECO and the Pro-CNIC Foundation. CNIO and CNIC are Severo Ochoa Centers of Excellence (MINECO awards SEV-2015-0510 and SEV-2015-0505, respectively).

Author information

Author notes

    • Marta Cañamero

    Present address: Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.

Affiliations

  1. Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

    • Guillermo de Cárcer
    • , Paulina Wachowicz
    • , Beatriz Escobar
    • , Alejandra González-Loyola
    • , Aicha El Bakkali
    •  & Marcos Malumbres
  2. Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Spanish National Cardiovascular Centre (CNIC), Madrid, Spain.

    • Sara Martínez-Martínez
    • , Jorge Oller
    • , Nerea Méndez-Barbero
    •  & Juan Miguel Redondo
  3. Centro de Investigaciones Biomédicas en RED (CIBERCV), Madrid, Spain.

    • Sara Martínez-Martínez
    • , Jorge Oller
    • , Luis J Jiménez-Borreguero
    •  & Juan Miguel Redondo
  4. Clare Hall Laboratories, London Research Institute, London, UK.

    • Tohru Takaki
  5. Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

    • Juan A Cámara
    •  & Francisca Mulero
  6. Advanced Imaging Unit, Spanish National Cardiovascular Centre (CNIC), and Cardiac Imaging Department, Hospital de la Princesa, Madrid, Spain.

    • Luis J Jiménez-Borreguero
  7. Centro de Investigación del Cáncer de Salamanca, University of Salamanca–CSIC, Salamanca, Spain.

    • Xosé R Bustelo
  8. Comparative Pathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

    • Marta Cañamero
  9. Department of Physiology and Pharmacology and Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.

    • María de los Ángeles Sevilla
    •  & María Jose Montero
  10. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.

    • Xosé R Bustelo
    • , María de los Ángeles Sevilla
    •  & María Jose Montero

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Contributions

G.d.C. performed most of the cellular and mouse experiments, with technical support from B.E. and A.E.B. P.W. generated the Plk1 alleles and performed initial experiments in Plk1 heterozygous mice and VSMCs. S.M.-M., J.O., N.M.-B., L.J.J.-B. and J.M.R. provided intellectual input on the cardiovascular studies and contributed to the phenotypic analysis of the vascular phenotype in mice. A.G.-L. helped with cellular and biochemical assays. J.A.C. and F.M. helped with echocardiography measurements. M.J.M. and M.d.l.A.S. performed the contractility and elasticity assays in the rings from aortas or the mesenteric arteries. X.R.B. provided intellectual input for the initial project design and further troubleshooting. T.T. studied the phosphorylation of Ect2 by Plk1. M.C. performed the histopathological analysis. G.d.C. and M.M. supervised the project and wrote the manuscript with the help of all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Guillermo de Cárcer or Juan Miguel Redondo or Marcos Malumbres.

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https://doi.org/10.1038/nm.4364