Skip to main content

Advertisement

SpringerLink
Log in

Augmentation of danusertib’s anticancer activity against melanoma by blockage of autophagy

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Previous evidence has shown that the increased expression of aurora kinase is closely related to melanoma progression and is an important therapeutic target in melanoma. Danusertib is an inhibitor of aurora kinase, and recent studies have shown that danusertib treatment induces autophagy in several types of cancer. Interestingly, autophagy plays a dual function in cancer as a pro-survival and anti-survival factor. In this study, we investigated the role of danusertib on the induction of autophagy in melanoma and determined the impact of autophagy induction on its anticancer activity against melanoma. Our results showed that danusertib can significantly inhibit melanoma growth by inducing cell cycle arrest and apoptosis. In addition, we demonstrated that danusertib treatment significantly inhibits the oncogenic Akt/mTOR signaling pathway and induces autophagy in melanoma cells. Furthermore, we identified that the inhibition of autophagy can enhance the inhibitory effects of danusertib on melanoma growth. Thus, the induction of autophagy by danusertib appears to be a survival mechanism in melanoma cells that may counteract its anticancer effects. These findings suggest a novel strategy to enhance the anticancer efficacy of danusertib in melanoma by blocking autophagy.

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
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Lo JA, Fisher DE. The melanoma revolution: from UV carcinogenesis to a new era in therapeutics. Science. 2014;346:945–9.

    Article  CAS  Google Scholar 

  2. Ma J, Guo W, Li C. Ubiquitination in melanoma pathogenesis and treatment. Cancer Med. 2017;6:1362–77.

    Article  Google Scholar 

  3. Chen J, Peng C, Lei L, Zhang J, Zeng W, Chen X. Nuclear envelope-distributed CD147 interacts with and inhibits the transcriptional function of RING1 and promotes melanoma cell motility. PLoS One. 2017;12:e0183689.

    Article  Google Scholar 

  4. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106–30.

    Article  Google Scholar 

  5. Bonet C, Giuliano S, Ohanna M, Bille K, Allegra M, Lacour JP, et al. Aurora B is regulated by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway and is a valuable potential target in melanoma cells. J Biol Chem. 2012;287:29887–98.

    Article  CAS  Google Scholar 

  6. Chang X, Zhang H, Lian S, Zhu W. miR-137 suppresses tumor growth of malignant melanoma by targeting aurora kinase A. Biochem Biophys Res Commun. 2016;475:251–6.

    Article  CAS  Google Scholar 

  7. Pacchierotti F, Adler ID, Eichenlaub-Ritter U, Mailhes JB. Gender effects on the incidence of aneuploidy in mammalian germ cells. Environ Res. 2007;104:46–69.

    Article  CAS  Google Scholar 

  8. Rong R, Jiang LY, Sheikh MS, Huang Y. Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation. Oncogene. 2007;26:7700–8.

    Article  CAS  Google Scholar 

  9. Dar AA, Zaika A, Piazuelo MB, Correa P, Koyama T, Belkhiri A, et al. Frequent overexpression of Aurora kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions. Cancer. 2008;112:1688–98.

    Article  CAS  Google Scholar 

  10. Chefetz I, Holmberg JC, Alvero AB, Visintin I, Mor G. Inhibition of Aurora-A kinase induces cell cycle arrest in epithelial ovarian cancer stem cells by affecting NFkB pathway. Cell Cycle. 2011;10:2206–14.

    Article  CAS  Google Scholar 

  11. Fenouille N, Tichet M, Dufies M, Pottier A, Mogha A, Soo JK, et al. The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion. PLoS One. 2012;7:e40378.

    Article  CAS  Google Scholar 

  12. Porcelli L, Guida G, Quatrale AE, Cocco T, Sidella L, Maida I, et al. Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy. J Transl Med. 2015;13:26.

    Article  Google Scholar 

  13. Liu Y, Hawkins OE, Su YJ, Vilgelm AE, Sobolik T, Thu YM, et al. Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-?B impairs this drug-induced senescence. EMBO Mol Med. 2013;5:149–66.

    Article  CAS  Google Scholar 

  14. Xie L, Meyskens FL Jr. The pan-Aurora kinase inhibitor, PHA-739358, induces apoptosis and inhibits migration in melanoma cell lines. Melanoma Res. 2013;23:102–13.

    Article  CAS  Google Scholar 

  15. Li JP, Yang YX, Liu QL, Zhou ZW, Pan ST, He ZX, et al. The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells. Drug Des Devel Ther. 2015;9:1027–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Yuan CX, Zhou ZW, Yang YX, He ZX, Zhang X, Wang D, et al. Danusertib, a potent pan-Aurora kinase and ABL kinase inhibitor, induces cell cycle arrest and programmed cell death and inhibits epithelial to mesenchymal transition involving the PI3K/Akt/mTOR-mediated signaling pathway in human gastric cancer AGS and NCI-N78 cells. Drug Des Devel Ther. 2015;9:1293–318.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Zi D, Zhou ZW, Yang YJ, Huang L, Zhou ZL, He SM, et al. Danusertib induces apoptosis, cell cycle arrest, and autophagy but inhibits epithelial to mesenchymal transition involving PI3K/Akt/mTOR signaling pathway in human ovarian cancer cells. Int J Mol Sci. 2015;16:27228–51.

    Article  CAS  Google Scholar 

  18. He SJ, Shu LP, Zhou ZW, Yang T, Duan W, Zhang X, et al. Inhibition of Aurora kinases induces apoptosis and autophagy via AURKB/p70S6K/RPL15 axis in human leukemia cells. Cancer Lett. 2016;382:215–30.

    Article  CAS  Google Scholar 

  19. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42.

    Article  CAS  Google Scholar 

  20. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75.

    Article  CAS  Google Scholar 

  21. Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res. 2002;62:7335–42.

    CAS  PubMed  Google Scholar 

  22. Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005;115:2679–88.

    Article  CAS  Google Scholar 

  23. Caporali S, Alvino E, Lacal PM, Levati L, Giurato G, Memoli D, et al. Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor. Int J Oncol. 2016;49:1164–74.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the First-Class Discipline Construction Founded Project of Ningxia Medical University (NXYLXK2017A05) and the School of Clinical Medicine and Ningxia Medical University 2018 university-level scientific research project (XM2018152).

Author information

Authors and Affiliations

  1. Department of Dermatology, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China

    Yuan-Yuan Shang, Nan Yu, Li Xia, Ying-Yao Yu, Chun-mei Ma, Ya-Ning Jiao & Yuan Wang

  2. Ningxia Medical University, Yinchuan, People’s Republic of China

    Yun-feng Li

  3. Department of Medical Genetics and Cell Biology, Ningxia Medical University, Yinchuan, People’s Republic of China

    Jie Dang

  4. Faculty of Medical Science, Kunming University of Science and Technology, No. 727, Jingming South Road, Chenggong District, Kunming, 650500, China

    Weichao Li

Authors
  1. Yuan-Yuan Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying-Yao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chun-mei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ya-Ning Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yun-feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jie Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Weichao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Yuan-Yuan Shang and Weichao Li conceived and designed this study. Yuan-Yuan Shang and Nan Yu Xu were responsible for doing the main experimental. Li Xia, Ying-Yao Yu, Chun-mei Ma, and Ya-Ning Jiao were responsible for construction of mice model. Yuan-Yuan Shang, Yun-feng Li, and Jie Dang were jointly involving in extracting data and writing the manuscript.

Corresponding author

Correspondence to Weichao Li.

Ethics declarations

This research was approved by the Research Ethics Board of the General Hospital of Ningxia Medical University.

Conflict of interest

The authors declare that they have no conflicts 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

Shang, YY., Yu, N., Xia, L. et al. Augmentation of danusertib’s anticancer activity against melanoma by blockage of autophagy. Drug Deliv. and Transl. Res. 10, 136–145 (2020). https://doi.org/10.1007/s13346-019-00668-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-019-00668-5

Keywords

Search

Navigation