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Cabazitaxel inhibits prostate cancer cell growth by inhibition of androgen receptor and heat shock protein expression

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Abstract

Purpose

Cabazitaxel, a semi-synthetic taxane of the third generation, inhibits prostate cancer (PC) cell growth by affecting the microtubule architecture. Since cabazitaxel has also been demonstrated to inhibit androgen receptor (AR) functionality, AR and AR-associated heat shock protein (HSP) expressions in the presence of cabazitaxel were characterized.

Methods

AR and HSP expressions were assessed via Western blotting utilizing a PC-cell-line in vitro system incubated with cabazitaxel.

Results

Incubation experiments with 0.3 nM cabazitaxel exhibited significantly reduced levels of AR and the AR-associated factors HSP90α, HSP40, and HSP70/HSP90 organising protein. Furthermore, expression of the anti-apoptotic factor HSP60 was suppressed. In contrast to other anticancer compounds, cabazitaxel did not alter the cytoprotective chemoresistance factor HSP27.

Conclusions

Despite the deregulation of microtubule organisation, cabazitaxel has been shown to suppress the expression of HSP. Very notably, and may be as a result of down-regulated HSP, cabazitaxel additionally inhibits the expression of the AR in AR-positive PC cells. Thus, cabazitaxel bears an additional anti-proliferative activity which is at least in part specific for PC cells.

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Abbreviations

PC:

Prostate cancer

AR:

Androgen receptor

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

ADT:

Androgen deprivation therapy

CRPC:

Castration-resistant prostate cancer

PSA:

Prostate-specific antigen

HSP:

Heat shock protein

HOP:

HSP70/HSP90-organising protein

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

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Acknowledgements

The authors thank Anne Brandenburg and Katja Wittig for excellent technical assistance.

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Authors and Affiliations

  1. Department of Urology, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany

    Anja-Martina Rottach, Hannes Ahrend, Benedikt Martin, Uwe Zimmermann, Martin Burchardt & Matthias B. Stope

  2. Department of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, 17475, Greifswald, Germany

    Reinhard Walther

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  1. Anja-Martina Rottach
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  2. Hannes Ahrend
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Contributions

AMR data collection and protocol development. HA data collection. BM data collection. RW data analysis and manuscript editing. UZ manuscript editing and data analysis. MB data analysis and manuscript editing. MBS protocol development, project management, data analysis, manuscript writing, and editing.

Corresponding author

Correspondence to Matthias B. Stope.

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Conflict of interest

By way of disclosure of conflict of interest, the compound cabazitaxel was kindly provided by Sanofi-Aventis Deutschland GmbH (Frankfurt/Main, Germany). The preparation of the manuscript for the present publication was financially supported by the company Sanofi-Aventis Deutschland GmbH. Sanofi-Aventis Deutschland GmbH has no influence on the published content. The authors alone are responsible for the scientific content of this publication.

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Rottach, AM., Ahrend, H., Martin, B. et al. Cabazitaxel inhibits prostate cancer cell growth by inhibition of androgen receptor and heat shock protein expression. World J Urol 37, 2137–2145 (2019). https://doi.org/10.1007/s00345-018-2615-x

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  • DOI: https://doi.org/10.1007/s00345-018-2615-x

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