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

Nature Communications
Govindi J SamaranayakePriyamvada Rai

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.

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Citations

Jul 21, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jing HuangChun Zhang
Sep 11, 2019·Nature Communications·Emre BaltaYvonne Samstag
May 13, 2019·Cancer Chemotherapy and Pharmacology·Jin-Jing JiaXian-Si Zeng
Aug 11, 2020·Oxidative Medicine and Cellular Longevity·Gan Huang, Shu-Ting Pan
Sep 17, 2020·International Journal of Molecular Sciences·Francesca CaponeSusan Costantini
Jan 16, 2021·Redox Biology·Ling ZhangPriyamvada Rai
Feb 16, 2021·Frontiers in Cell and Developmental Biology·Emre BaltaYvonne Samstag
Mar 5, 2021·Molecular Biology Reports·Jin-Ming Zhao, Tong-Gang Qi
Sep 23, 2020·International Journal of Biological Macromolecules·Nikhilesh JoardarSanti P Sinha Babu
Oct 17, 2020·BioMed Research International·Chenglin HanXunbo Jin
Aug 15, 2021·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Bogdan JovanovicGeorg Stoecklin
Mar 25, 2019·Cancer Letters·Sankaralingam SaikolappanHari K Koul

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Methods Mentioned

BETA
xenograft
Assay
scraping
Protein Assay
PCR
ELISA

Software Mentioned

R
ImageJ Cell Counter Plugin
ImageJ Analyze Gels ( NIH )
StepOne
limma
GraphPad Prism
bioconductor package lumi

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