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PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin

Nature Medicine volume 20, pages 741–747 (2014)Cite this article

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A Corrigendum to this article was published on 07 May 2015

A Corrigendum to this article was published on 08 October 2014

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Abstract

The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1–urokinase-type plasminogen activator (uPA)–uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1–uPA–uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.

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Figure 1: 16K PRL interacts with PAI-1.
Figure 2: Inhibition of B16F10 tumor growth by 16K PRL is PAI-1 dependent.
Figure 3: Inhibition of keratinocyte tumor growth by 16K PRL is PAI-1 dependent.
Figure 4: PAI-1 is required for 16K PRL to impair neovascularization.
Figure 5: The in vitro antiangiogenic effects of 16K PRL require PAI-1–uPA–uPAR.
Figure 6: 16K PRL inhibits the antifibrinolytic activity of PAI-1.

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  • 25 August 2014

     In the version of this article initially published, it was stated that 16K PRL levels are increased in retinopathy, citing reference 10. However, this reference was cited incorrectly, and in fact another paper showed that 16K PRL levels are decreased in diabetic retinopathy. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J.-M. Foidart for helpful discussions. We also thank A. Igout, O. Jacquin and M. Galleni for assisting with SPR, E. Rozet for helping with statistical analysis, R. Lijnen (Center for Molecular and Vascular Biology) for providing the PAI-1 ELISA and N. Fusenig (German Cancer Research) for providing BD VII cells. We thank the technology platforms support staff at the GIGA Research Center and P. Drion of the mouse facility (GIGA). This study was supported by the University of Liège, the Fonds pour la Recherche Industrielle et Agricole (FRIA), Belgium, the Fonds National de la Recherche Scientifique (FNRS), Belgium, the Belgian Federal Science Policy Office grant IUAP06/30 (to I.S., A.N. and P.C.), Neoangio program grant no. 616476 from the 'Service Public de Wallonie' (to I.S. and A.N.), the Belgian Foundation against Cancer, Televie, the Léon Frédéricq Fund and the Centre Anticancéreux (Liège, Belgium) and Dutch Cancer Society grants UM2008-4101 and VU2009-4358 (to V.L.T. and A.W.G.). The work of P.C. is supported by the Belgian Science Policy (IAP no. P7/03), the Leducq Network of Excellence, the Flanders Research Foundation (FWO), the Foundation against Cancer, European Research Council Advanced Research Grant EU-ERC269073 and long-term structural Methusalem funding by the Flemish Government.

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Author notes

  1. Khalid Bajou and Stephanie Herkenne: These authors contributed equally to this work.

  2. Joseph A Martial and Peter Carmeliet: These authors jointly supervised this work.

Authors and Affiliations

  1. Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium

    Khalid Bajou, Stephanie Herkenne, Salvino D'Amico, Ngoc-Quynh-Nhu Nguyen, Sébastien Tabruyn, Mohammed Srahna, Jean-Yves Carabin, Olivier Nivelles, Cécile Paques, Michelle Lion, Joseph A Martial & Ingrid Struman

  2. Department of Medical Oncology, Angiogenesis Laboratory, VU University Medical Center, Amsterdam, the Netherlands

    Victor L Thijssen & Arjan W Griffioen

  3. Department of Radiotherapy, VU University Medical Center, Amsterdam, the Netherlands

    Victor L Thijssen

  4. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center (VRC), VIB, Leuven, Belgium

    Ann Bouché, Ivo Cornelissen, Stefan Vinckier, Mieke Dewerchin & Peter Carmeliet

  5. Department of Oncology, Laboratory of Angiogenesis & Neurovascular Link, KU Leuven, Leuven, Belgium

    Ann Bouché, Ivo Cornelissen, Stefan Vinckier, Mieke Dewerchin & Peter Carmeliet

  6. Unit of Biology of Tumor and Development, GIGA Research Center, University of Liège, Liège, Belgium

    Agnès Noel

  7. Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium

    Ann Gils & Paul J Declerck

Authors
  1. Khalid Bajou
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Contributions

K.B. and S.H. designed, supervised and conducted the experiments, performed in vitro and in vivo studies and statistical analyses, interpreted the data and wrote the manuscript. K.B. performed tumor studies, Matrigel plug assays and pulmonary embolism and in vitro studies. S.H., N.-Q.-N.N. and O.N. performed arterial thrombolysis experiments. S.H., S.T., O.N. and S.V. performed retinal angiogenesis experiments. V.L.T. and A.W.G. participated in designing the yeast two-hybrid experiments and in data interpretation. S.D. performed the SPR studies. J.-Y.C. participated in in vitro and in vivo studies. C.P. and M.L. participated in in vitro studies. M.S. performed immunohistochemistry staining and analysis. A.N. participated in data analysis, provided scientific suggestions and contributed to the manuscript review. A.G. and P.J.D. performed the SPR analyses and participated in experiments on PAI-1 antiproteolytic activities. A.B., I.C. and S.V. contributed to in vivo experiment analysis and setup. J.A.M. conceived the study and revised the manuscript. M.D. and P.C. contributed to the experimental analysis and setup and participated in writing the manuscript. I.S. conceived and designed the study, performed yeast-two-hybrid screening, coordinated the experiments and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ingrid Struman.

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Bajou, K., Herkenne, S., Thijssen, V. et al. PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat Med 20, 741–747 (2014). https://doi.org/10.1038/nm.3552

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