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Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression

Oncogene volume 34, pages 3700–3710 (2015)Cite this article

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Abstract

Androgen receptor splicing variants (ARVs) that lack the ligand-binding domain (LBD) are associated with the development of castration-resistant prostate cancer (CRPC), including resistance to the new generation of high-affinity anti-androgens. However, the mechanism by which ARV expression is regulated is not fully understood. In this study, we show that the activation of classical nuclear factor-kappa B (NF-κB) signaling increases the expression of ARVs in prostate cancer (PCa) cells and converts androgen-sensitive PCa cells to become androgen-insensitive, whereas downregulation of NF-κB signaling inhibits ARV expression and restores responsiveness of CRPC to anti-androgen therapy. In addition, we demonstrated that combination of anti-androgen with NF-κB-targeted therapy inhibits efficiently tumor growth of human CRPC xenografts. These results indicate that induction of ARVs by activated NF-κB signaling in PCa cells is a critical mechanism by which the PCa progresses to CRPC. This has important implications as it can prolong the survival of CRPC patients by restoring the tumors to once again respond to conventional androgen-deprivation therapy (ADT).

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Acknowledgements

We thank Dr Martin Leverkus (University of Magdeburg, Germany) for providing us with IKK2-EE and IKK2-KD retroviral vectors, and Tom C Case and Manik Paul for technical assistance. This work was supported to RJ by the Department of Defense (DOD) Prostate Cancer Research Program (PCRP; W81XWH-10-1-0236); to RJM by the National Cancer Institute (4R01 CA076142-14) and the Frances Preston Laboratories of the TJ Martell Foundation.

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  1. Department of Urologic Surgery, Vanderbilt Prostate Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA

    R Jin, H Yamashita, X Yu, J Wang, O E Franco, Y Wang, S W Hayward & R J Matusik

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  1. R Jin
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Correspondence to R Jin.

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Jin, R., Yamashita, H., Yu, X. et al. Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression. Oncogene 34, 3700–3710 (2015). https://doi.org/10.1038/onc.2014.302

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