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Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

Oncogene volume 35, pages 6065–6076 (2016)Cite this article

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Abstract

Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) and are associated with PCa progression. As the current androgen deprivation therapy with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here, we found NEPCa cells could increase the docetaxel resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed that NEPCa could increase the docetaxel resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or shPTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa.

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Acknowledgements

This work was supported by NIH grants (CA155477 and CA156700), George Whipple Professorship Endowment and Taiwan Department of Health Clinical Trial, Research Center of Excellence (DOH99-TD-B-111-004 to China Medical University, Taichung, Taiwan) and China 973 Program (2012CB518305). We thank Karen Wolf for help in preparing the manuscript.

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  1. Department of Urology, Peking University/First Hospital, Beijing, China

    Y Cui, S Hu, X Li & J Jin

  2. Departments of Pathology, George Whipple Lab for Cancer Research, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA

    Y Cui, Y Sun, S Hu, J Luo, L Li, S Yeh & C Chang

  3. Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan

    C Chang

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Cui, Y., Sun, Y., Hu, S. et al. Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals. Oncogene 35, 6065–6076 (2016). https://doi.org/10.1038/onc.2016.135

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