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Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer

Author

Listed:
  • Govindi J. Samaranayake

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Clara I. Troccoli

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Mai Huynh

    (University of Miami Miller School of Medicine
    University of Miami Undergraduate Research and Community Outreach Program)

  • Rolando D. Z. Lyles

    (University of Miami Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Karen Kage

    (University of Miami Miller School of Medicine)

  • Andrew Win

    (University of Miami Miller School of Medicine
    University of Miami Undergraduate Research and Community Outreach Program)

  • Vishalakshi Lakshmanan

    (University of Miami Miller School of Medicine
    University of Miami Undergraduate Research and Community Outreach Program)

  • Deukwoo Kwon

    (Sylvester Comprehensive Cancer Center)

  • Yuguang Ban

    (Sylvester Comprehensive Cancer Center)

  • Steven Xi Chen

    (Sylvester Comprehensive Cancer Center
    University of Miami Miller School of Medicine)

  • Enrique Rodriguez Zarco

    (University of Miami Miller School of Medicine)

  • Merce Jorda

    (Sylvester Comprehensive Cancer Center
    University of Miami Miller School of Medicine)

  • Kerry L. Burnstein

    (Sylvester Comprehensive Cancer Center
    University of Miami Miller School of Medicine)

  • Priyamvada Rai

    (University of Miami Miller School of Medicine
    Sylvester Comprehensive Cancer Center)

Abstract

Androgen deprivation (AD) therapy failure leads to terminal and incurable castration-resistant prostate cancer (CRPC). We show that the redox-protective protein thioredoxin-1 (TRX1) increases with prostate cancer progression and in androgen-deprived CRPC cells, suggesting that CRPC possesses an enhanced dependency on TRX1. TRX1 inhibition via shRNA or a phase I-approved inhibitor, PX-12 (untested in prostate cancer), impedes the growth of CRPC cells to a greater extent than their androgen-dependent counterparts. TRX1 inhibition elevates reactive oxygen species (ROS), p53 levels and cell death in androgen-deprived CRPC cells. Unexpectedly, TRX1 inhibition also elevates androgen receptor (AR) levels under AD, and AR depletion mitigates both TRX1 inhibition-mediated ROS production and cell death, suggesting that AD-resistant AR expression in CRPC induces redox vulnerability. In vivo TRX1 inhibition via shRNA or PX-12 reverses the castration-resistant phenotype of CRPC cells, significantly inhibiting tumor formation under systemic AD. Thus, TRX1 is an actionable CRPC therapeutic target through its protection against AR-induced redox stress.

Suggested Citation

  • Govindi J. Samaranayake & Clara I. Troccoli & Mai Huynh & Rolando D. Z. Lyles & Karen Kage & Andrew Win & Vishalakshi Lakshmanan & Deukwoo Kwon & Yuguang Ban & Steven Xi Chen & Enrique Rodriguez Zarco, 2017. "Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01269-x
    DOI: 10.1038/s41467-017-01269-x
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    Cited by:

    1. Chandra Bhushan Prasad & Adrian Oo & Yujie Liu & Zhaojun Qiu & Yaogang Zhong & Na Li & Deepika Singh & Xiwen Xin & Young-Jae Cho & Zaibo Li & Xiaoli Zhang & Chunhong Yan & Qingfei Zheng & Qi-En Wang &, 2024. "The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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