Skip to main content

Advertisement

SpringerLink
Log in

YLZ-F5, a novel polo-like kinase 4 inhibitor, inhibits human ovarian cancer cell growth by inducing apoptosis and mitotic defects

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Polo-like kinase 4 (PLK4), a member of the polo-like kinase family, plays several important roles in mitotic regulation, including centrosome duplication, spindle formation, and cytokinesis. PLK4 overexpression is frequently detected in many human cancers, including ovarian cancer, and the inhibition of PLK4 activity results in cancer cell mitotic arrest and apoptosis. Therefore, PLK4 might be a valid therapeutic target for antitumor therapy. In the present study, we aimed to determine if YLZ-F5, a potent small-molecule inhibitor of PLK4, inhibits ovarian cancer cell growth.

Methods and results

MTT assay showed that YLZ-F5 inhibited ovarian cancer cell proliferation in a concentration- and time-dependent manner. The results of colony formation assays were consistent with those of the MTT assay results. In addition, YLZ-F5 induced ovarian cancer cell apoptosis that was associated with activation of caspase-3/caspase-9. Moreover, YLZ-F5 caused aberrant in centriole duplication that was associated with the inhibition of PLK4 phosphorylation. Notably, we showed that YLZ-F5 promoted the accumulation of ovarian cancer cells with mitotic defects (> 4 N DNA content) in a concentration-dependent manner. Furthermore, YLZ-F5 markedly inhibited the migration of A2780 cells.

Conclusion

Taken together, these findings suggest that YLZ-F5 is a potential drug candidate for human ovarian cancer.

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

Access this article

Log in via an institution

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
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

PLK4:

Polo-like kinase 4

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-di-phenyl-2H-tetrazolium bromide

TCGA:

The Cancer Genome Atlas

NMR:

Nuclear magnetic resonance

ESI–MS:

Electrospray ionisation-mass spectrometry

DMSO:

Dimethyl sulfoxide

PI:

Propidium iodide

DAPI:

2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride

7-AAD:

7-Aminoactinomycin D

ECL:

Enhanced chemiluminescence

GEPIA:

Gene expression profiling interactive analyze

FIGO:

International Federation of Gynecology and Obstetrics

PFS:

Progression-free survival

OS:

Overall survival

References

  1. Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551

    Article  PubMed  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132. https://doi.org/10.3322/caac.21338

    Article  PubMed  Google Scholar 

  3. Cress RD, Chen YS, Morris CR, Petersen M, Leiserowitz GS (2015) Characteristics of long-term survivors of epithelial ovarian cancer. Obstet Gynecol 126(3):491. https://doi.org/10.1097/AOG.0000000000000981

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lheureux S, Gourley C, Vergote I, Oza AM (2019) Epithelial ovarian cancer. Lancet 393(10177):1240–1253. https://doi.org/10.1016/S0140-6736(18)32552-2

    Article  PubMed  Google Scholar 

  5. Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY (2016) Ovarian cancer. Nat Rev Dis Primers 2:16061. https://doi.org/10.1038/nrdp.2016.61

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cancer Genome Atlas Research N (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474(7353):609–615. https://doi.org/10.1038/nature10166

    Article  CAS  Google Scholar 

  7. de Carcer G, Manning G, Malumbres M (2011) From Plk1 to Plk5: functional evolution of polo-like kinases. Cell Cycle 10(14):2255–2262. https://doi.org/10.4161/cc.10.14.16494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barr FA, Silljé HH, Nigg EA (2004) Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 5(6):429. https://doi.org/10.1038/nrm1401

    Article  CAS  PubMed  Google Scholar 

  9. Archambault V, Glover DM (2009) Polo-like kinases: conservation and divergence in their functions and regulation. Nat Rev Mol Cell Biol 10(4):265. https://doi.org/10.1038/nrm2675

    Article  CAS  PubMed  Google Scholar 

  10. Takai N, Hamanaka R, Yoshimatsu J, Miyakawa I (2005) Polo-like kinases (Plks) and cancer. Oncogene 24(2):287–291. https://doi.org/10.1038/sj.onc.1208272

    Article  CAS  PubMed  Google Scholar 

  11. Lens SM, Voest EE, Medema RH (2010) Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer 10(12):825. https://doi.org/10.1038/nrc2964

    Article  CAS  PubMed  Google Scholar 

  12. Archambault V, Lepine G, Kachaner D (2015) Understanding the Polo Kinase machine. Oncogene 34(37):4799–4807. https://doi.org/10.1038/onc.2014.451

    Article  CAS  PubMed  Google Scholar 

  13. Strebhardt K (2010) Multifaceted polo-like kinases: drug targets and antitargets for cancer therapy. Nat Rev Drug Discov 9(8):643. https://doi.org/10.1038/nrd3184

    Article  CAS  PubMed  Google Scholar 

  14. Leung GC, Hudson JW, Kozarova A, Davidson A, Dennis JW, Sicheri F (2002) The Sak polo-box comprises a structural domain sufficient for mitotic subcellular localization. Nat Struct Biol 9(10):719–724. https://doi.org/10.1038/nsb848

    Article  CAS  PubMed  Google Scholar 

  15. Sillibourne JE, Bornens M (2010) Polo-like kinase 4: the odd one out of the family. Cell Div 5(1):25. https://doi.org/10.1186/1747-1028-5-25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Habedanck R, Stierhof Y-D, Wilkinson CJ, Nigg EA (2005) The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 7(11):1140. https://doi.org/10.1038/ncb1320

    Article  CAS  PubMed  Google Scholar 

  17. Holland AJ, Lan W, Niessen S, Hoover H, Cleveland DW (2010) Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability. J Cell Biol 188(2):191–198. https://doi.org/10.1083/jcb.200911102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Takai N, Miyazaki T, Fujisawa K, Nasu K, Hamanaka R, Miyakawa I (2001) Expression of polo-like kinase in ovarian cancer is associated with histological grade and clinical stage. Cancer Lett 164(1):41–49. https://doi.org/10.1016/s0304-3835(00)00703-5

    Article  CAS  PubMed  Google Scholar 

  19. Weichert W, Denkert C, Schmidt M, Gekeler V, Wolf G, Kobel M, Dietel M, Hauptmann S (2004) Polo-like kinase isoform expression is a prognostic factor in ovarian carcinoma. Br J Cancer 90(4):815–821. https://doi.org/10.1038/sj.bjc.6601610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. He Y, Wang H, Yan M, Yang X, Shen R, Ni X, Chen X, Yang P, Chen M, Lu X et al (2018) High LIN28A and PLK4 coexpression is associated with poor prognosis in epithelial ovarian cancer. Mol Med Rep 18(6):5327–5336. https://doi.org/10.3892/mmr.2018.9562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu Z, Lei Q, Wei W, Xiong L, Shi Y, Yan G, Gao C, Ye T, Wang N, Yu L (2017) Synthesis and biological evaluation of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as PLK4 inhibitors for the treatment of breast cancer. RSC Adv 7(44):27737–27746. https://doi.org/10.1039/C7RA02518A

    Article  CAS  Google Scholar 

  22. Lei Q, Xiong L, Xia Y, Feng Z, Gao T, Wei W, Song X, Ye T, Wang N, Peng C et al (2018) YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect. Cell Death Dis 9(11):1066. https://doi.org/10.1038/s41419-018-1071-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Holland AJ, Cleveland DW (2014) Polo-like kinase 4 inhibition: a strategy for cancer therapy? Cancer Cell 26(2):151–153. https://doi.org/10.1016/j.ccr.2014.07.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mason JM, Lin DC, Wei X, Che Y, Yao Y, Kiarash R, Cescon DW, Fletcher GC, Awrey DE, Bray MR et al (2014) Functional characterization of CFI-400945, a polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell 26(2):163–176. https://doi.org/10.1016/j.ccr.2014.05.006

    Article  CAS  PubMed  Google Scholar 

  25. Nigg EA, Raff JW (2009) Centrioles, centrosomes, and cilia in health and disease. Cell 139(4):663–678. https://doi.org/10.1016/j.cell.2009.10.036

    Article  CAS  PubMed  Google Scholar 

  26. Zhao Y, Wang X (2019) PLK4: a promising target for cancer therapy. J Cancer Res Clin Oncol 145(10):2413–2422. https://doi.org/10.1007/s00432-019-02994-0

    Article  PubMed  Google Scholar 

  27. Kazazian K, Go C, Wu H, Brashavitskaya O, Xu R, Dennis JW, Gingras A-C, Swallow CJ (2017) Plk4 promotes cancer invasion and metastasis through Arp2/3 complex regulation of the actin cytoskeleton. Can Res 77(2):434–447. https://doi.org/10.1158/0008-5472.CAN-16-2060

    Article  CAS  Google Scholar 

  28. Tian X, Zhou D, Chen L, Tian Y, Zhong B, Cao Y, Dong Q, Zhou M, Yan J, Wang Y (2018) Polo-like kinase 4 mediates epithelial–mesenchymal transition in neuroblastoma via PI3K/Akt signaling pathway. Cell Death Dis 9(2):54. https://doi.org/10.1038/s41419-017-0088-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Press MF, Xie B, Davenport S, Zhou Y, Guzman R, Nolan GP, O'Brien N, Palazzolo M, Mak TW, Brugge JS et al (2019) Role for polo-like kinase 4 in mediation of cytokinesis. Proc Natl Acad Sci USA 116(23):11309–11318. https://doi.org/10.1073/pnas.1818820116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kawakami M, Mustachio LM, Zheng L, Chen Y, Rodriguez-Canales J, Mino B, Kurie JM, Roszik J, Villalobos PA, Thu KL et al (2018) Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers. Proc Natl Acad Sci USA 115(8):1913–1918. https://doi.org/10.1073/pnas.1719760115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liao Z, Zhang H, Fan P, Huang Q, Dong K, Qi Y, Song J, Chen L, Liang H, Chen X, Zhang Z, Zhang B (2019) High PLK4 expression promotes tumor progression and induces epithelial-mesenchymal transition by regulating the Wnt/β-catenin signaling pathway in colorectal cancer. Int J Oncol 54(2):479–490. https://doi.org/10.3892/ijo.2018.4659

    Article  CAS  PubMed  Google Scholar 

  32. Kazazian K, Go C, Wu H, Brashavitskaya O, Xu R, Dennis JW, Gingras AC, Swallow CJ (2017) Plk4 promotes cancer invasion and metastasis through Arp2/3 complex regulation of the actin cytoskeleton. Cancer Res 77(2):434–447. https://doi.org/10.1158/0008-5472.CAN-16-2060

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the China Postdoctoral Science Foundation [Grant number 2019M652543] and Sichuan Provincial Science and technology program for Key research and development, China (No. 2018SZ0007).

Author information

Author notes

  1. Yongxia Zhu and Zhihao Liu contributed equally.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No. 7 Weiwu Road, Zhengzhou, 450003, Henan, China

    Yongxia Zhu, Meiqin Yang, Xiaoyi Li, Zhaodi Wang, Xueqin Wang & Yue Wang

  2. State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China

    Zhihao Liu, Yanling Qu, Jun Zeng & Luoting Yu

  3. Medical Genetics Institute of Henan Province, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450003, China

    Junxiang Su

Authors
  1. Yongxia Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhihao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanling Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meiqin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhaodi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junxiang Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xueqin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luoting Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Luoting Yu or Yue Wang.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Y., Liu, Z., Qu, Y. et al. YLZ-F5, a novel polo-like kinase 4 inhibitor, inhibits human ovarian cancer cell growth by inducing apoptosis and mitotic defects. Cancer Chemother Pharmacol 86, 33–43 (2020). https://doi.org/10.1007/s00280-020-04098-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-020-04098-w

Keywords

Search

Navigation