Skip to main content

Advertisement

Springer Nature Link
Log in

Polo-like kinase inhibitor BI2536 induces eryptosis

Polo-like-Kinase-Inhibitor BI2536 induziert Eryptose

  • original article
  • Published:
Wiener Medizinische Wochenschrift Aims and scope Submit manuscript

Summary

BI2536 is potent inhibitor of polo-like kinases PLK1, 2, and 3. The inhibition of PLKs in nucleated cells induces apoptosis by perturbing the cell cycle with consequent engagement of mitotic catastrophe. BI2536 is being tested as chemotherapy in various phase I/II/III clinical trials. Erythrocytes do not have a nucleus; however, they may undergo programmed suicide with characteristic hallmarks including cell shrinkage and phosphatidylserine translocation to the cell surface. This particular death is baptized eryptosis. Our study explored whether BI2536 induces eryptosis. We used flow cytometry to access death in red blood cells. We analyzed the cellular volume, the intracellular calcium concentration, the cell surface phosphatidylserine exposure, and the ceramide abundance. In addition, we analyzed the effect of BI2536 on hemolysis. Our investigation showed that after 48 h of incubation with PLK inhibitor BI2536, erythrocytes lost volume and were positive for annexin‑V without any effect on hemolysis. Cells also showed an abundance of ceramide and an increase of intracellular calcium. All these finding suggest that BI2536 provokes eryptosis in red blood cells, ostensibly in part due to Ca2+ entry and ceramide accumulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol. 2004;5:429–40.

    Article  CAS  PubMed  Google Scholar 

  2. Schmucker S, Sumara I. Molecular dynamics of PLK1 during mitosis. Mol Cell Oncol. 2014;1:e954507.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cizmecioglu O, Warnke S, Arnold M, Duensing S, Hoffmann I. Plk2 regulated centriole duplication is dependent on its localization to the centrioles and a functional polo-box domain. Cell Cycle. 2008;7:3548–55.

    Article  CAS  PubMed  Google Scholar 

  4. Xie S, et al. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J Biol Chem. 2001;276:43305–12.

    Article  CAS  PubMed  Google Scholar 

  5. Jemaà M, Kifagi C, Serrano SS, Massoumi R. Preferential killing of tetraploid colon cancer cells by targeting the mitotic Kinase PLK1. Cell Physiol Biochem. 2020;54:303–20.

    Article  PubMed  Google Scholar 

  6. Steegmaier M, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17:316–22.

    Article  CAS  PubMed  Google Scholar 

  7. Manic G, Corradi F, Sistigu A, Siteni S, Vitale I. Molecular regulation of the spindle assembly checkpoint by kinases and phosphatases. Int Rev Cell Mol Biol. 2017;328:105–61.

    Article  CAS  PubMed  Google Scholar 

  8. Jemaà M. Mitotic spindle as therapeutic target for tetraploid cancer cells. Eurasian J Med Oncol. 2021;5(3):205–8.

    Google Scholar 

  9. D’Alessandro A, Dzieciatkowska M, Nemkov T, Hansen KC. Red blood cell proteomics update: Is there more to discover? Blood Transfus. 2017;15:182–7.

    PubMed  PubMed Central  Google Scholar 

  10. Garcia-Roa M, et al. Red blood cell storage time and transfusion: current practice, concerns and future perspectives. Blood Transfus. 2017;15:222–31.

    PubMed  PubMed Central  Google Scholar 

  11. Mairbaurl H, Weber RE. Oxygen transport by hemoglobin. Compr Physiol. 2012;2:1463–89.

    Article  PubMed  Google Scholar 

  12. Moras M, Lefevre SD, Ostuni MA. From erythroblasts to mature red blood cells: organelle clearance in mammals. Front Physiol. 2017;8:1076.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kaestner L, Bogdanova A. Regulation of red cell life-span, erythropoiesis, senescence, and clearance. Front Physiol. 2014;5:269.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lang E, Lang F. Triggers, inhibitors, mechanisms, and significance of eryptosis: the suicidal erythrocyte death. Biomed Res Int. 2015;2015:513518.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Foller M, Lang F. Ion transport in eryptosis, the suicidal death of erythrocytes. Front Cell Dev Biol. 2020;8:597.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lang F, Jilani K, Lang E. Therapeutic potential of manipulating suicidal erythrocyte death. Expert Opin Ther Targets. 2015;19:1219–27.

    Article  CAS  PubMed  Google Scholar 

  17. Qadri SM, Bissinger R, Solh Z, Oldenborg PA. Eryptosis in health and disease: a paradigm shift towards understanding the (patho)physiological implications of programmed cell death of erythrocytes. Blood Rev. 2017;31:349–61.

    Article  CAS  PubMed  Google Scholar 

  18. Lang F, et al. Eryptosis, a window to systemic disease. Cell Physiol Biochem. 2008;22:373–80.

    Article  CAS  PubMed  Google Scholar 

  19. Yoshida T, Prudent M, D’Alessandro A. Red blood cell storage lesion: causes and potential clinical consequences. Blood Transfus. 2019;17:27–52.

    PubMed  PubMed Central  Google Scholar 

  20. Jemaà M, et al. Stimulation of suicidal erythrocyte death by the CDC25 inhibitor NSC-95397. Cell Physiol Biochem. 2016;40:597–607.

    Article  PubMed  Google Scholar 

  21. Fezai M, Slaymi C, Ben-Attia M, Lang F, Jemaà M. Purified lesser weever fish venom (Trachinus vipera) induces eryptosis, apoptosis and cell cycle arrest. Sci Rep. 2016;6:39288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jemaà M, Fezai M, Bissinger R, Lang F. Methods employed in cytofluorometric assessment of eryptosis, the suicidal erythrocyte death. Cell Physiol Biochem. 2017;43:431–44.

    Article  PubMed  Google Scholar 

  23. Lang E, Bissinger R, Gulbins E, Lang F. Ceramide in the regulation of eryptosis, the suicidal erythrocyte death. Apoptosis. 2015;20:758–67.

    Article  CAS  PubMed  Google Scholar 

  24. Lang E, Lang F. Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin Cell Dev Biol. 2015;39:35–42.

    Article  CAS  PubMed  Google Scholar 

  25. Lang F, Huber SM, Szabo I, Gulbins E. Plasma membrane ion channels in suicidal cell death. Arch Biochem Biophys. 2007;462:189–94.

    Article  CAS  PubMed  Google Scholar 

  26. Lang F, Lang KS, Lang PA, Huber SM, Wieder T. Mechanisms and significance of eryptosis. Antioxid Redox Signal. 2006;8:1183–92.

    Article  CAS  PubMed  Google Scholar 

  27. Lang E, Qadri SM, Lang F. Killing me softly—suicidal erythrocyte death. Int J Biochem Cell Biol. 2012;44:1236–43.

    Article  CAS  PubMed  Google Scholar 

  28. Lang F, Bissinger R, Abed M, Artunc F. Eryptosis—the neglected cause of anemia in end stage renal disease. Kidney Blood Press Res. 2017;42:749–60.

    Article  CAS  PubMed  Google Scholar 

  29. Al Mamun Bhuyan A, et al. Inhibition of suicidal erythrocyte death by volasertib. Cell Physiol Biochem. 2017;43:1472–86.

    Article  PubMed  Google Scholar 

  30. Tischer J, Gergely F. Anti-mitotic therapies in cancer. J Cell Biol. 2019;218:10–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gohda J, et al. BI-2536 and BI-6727, dual polo-like kinase/bromodomain inhibitors, effectively reactivate latent HIV‑1. Sci Rep. 2018;8:3521.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Raab CA, Raab M, Becker S, Strebhardt K. Non-mitotic functions of polo-like kinases in cancer cells. Biochim Biophys Acta Rev Cancer. 2021;1875:188467.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the laboratory of molecular biotechnology of eukaryotes (Sfax) and the Department of Physiology I (Tübingen) members for their support. The authors acknowledge the meticulous preparation of the manuscript by Learn & Win (https://learn2w.weebly.com).

Author information

Authors and Affiliations

  1. Laboratory of Molecular Biotechnology of Eukaryotes, Sfax Biotechnology Centre, Sfax University, Sfax, Tunisia

    Mohamed Jemaà & Raja Mokdad Gargouri

  2. Department of Physiology I, Eberhard-Karls University Tübingen, Tübingen, Germany

    Florian Lang

Authors
  1. Mohamed Jemaà
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Raja Mokdad Gargouri
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Florian Lang
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

M.J. developed the concept, and designed and performed experiments. M.J., F.L., and R.M.G analyzed data and wrote the manuscript. All authors reviewed the manuscript.

Corresponding author

Correspondence to Mohamed Jemaà.

Ethics declarations

Conflict of interest

M. Jemaà, R. Mokdad Gargouri, and F. Lang declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

M.J. and F.L. share senior co-authorship.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jemaà, M., Mokdad Gargouri, R. & Lang, F. Polo-like kinase inhibitor BI2536 induces eryptosis. Wien Med Wochenschr 173, 152–157 (2023). https://doi.org/10.1007/s10354-022-00966-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10354-022-00966-7

Keywords