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

Govindi J. Samaranayake, Clara I. Troccoli, Mai Huynh, Rolando D.Z. Lyles, Karen Kage, Andrew Win, Vishalakshi Lakshmanan, Deukwoo Kwon, Yuguang Ban, Xi Chen, Enrique Rodriguez Zarco, Merce Jorda, Kerry L Burnstein, Priyamvada Rai

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Article number1204
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Samaranayake, G. J., Troccoli, C. I., Huynh, M., Lyles, R. D. Z., Kage, K., Win, A., Lakshmanan, V., Kwon, D., Ban, Y., Chen, X., Zarco, E. R., Jorda, M., Burnstein, K. L., & Rai, P. (2017). Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer. Nature Communications, 8(1), [1204]. https://doi.org/10.1038/s41467-017-01269-x