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Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner

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Abstract

Purpose

At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive.

Methods

In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC.

Results

Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment.

Conclusions

In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance.

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Acknowledgements

We thanked Dr. Yang Sun for proof reading of our manuscript, and sincerely thanked the generous help from all the members of the Department of Urology, Shandong Provincial Qianfoshan Hospital, Shandong University.

Funding

This work was supported by the National Natural Science Foundation of China (8180060968).

Author information

Author notes

  1. Fei Wu and Yun Lin are co-first authors and have contributed equally to this article.

Authors and Affiliations

  1. Department of Urology, Shandong Provincial Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, People’s Republic of China

    Fei Wu, Yun Lin, Hongyun Li, Lechao Zhang, Zeqiang Sun, Shengliang Huang, Shun Li, Shiming Huang, Qingli Zhao & Qingyong Liu

  2. Department of Out-Patient, No. 88 Hospital of PLA, Tai’an, 271000, People’s Republic of China

    Peng Cui

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  1. Fei Wu
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  2. Yun Lin
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  4. Hongyun Li
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  5. Lechao Zhang
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  11. Qingyong Liu
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Corresponding authors

Correspondence to Fei Wu or Qingyong Liu.

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The authors declare no conflict of interest in this study.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Wu, F., Lin, Y., Cui, P. et al. Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner. Cancer Chemother Pharmacol 81, 999–1006 (2018). https://doi.org/10.1007/s00280-018-3578-8

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  • DOI: https://doi.org/10.1007/s00280-018-3578-8

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