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

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.

Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway

“…Thioredoxin‐1 (TRX1) is 12‐kDa thiol redox‐active protein that is believed to protect individuals from oxidative stress‐induced damage by scavenging ROS. TRX1 is translocated into the nucleus to regulate the activity of transcription factors such as activator protein‐1, NF‐κB and p53, and plays an important role in the regulation of cell viability and activation . An elevated level of TRX1 is found in various human cancers, such as lung, liver, colorectal and prostate cancers, as compared to their respective normal tissues .…”

“…TRX1 is translocated into the nucleus to regulate the activity of transcription factors such as activator protein‐1, NF‐κB and p53, and plays an important role in the regulation of cell viability and activation . An elevated level of TRX1 is found in various human cancers, such as lung, liver, colorectal and prostate cancers, as compared to their respective normal tissues . In addition, enhanced TRX1 levels are often reported in many types of cancers that have progressed, metastasized or become resistant to chemotherapy .…”

“…In addition, enhanced TRX1 levels are often reported in many types of cancers that have progressed, metastasized or become resistant to chemotherapy . For instance, castration‐resistant prostate cancer cells showed enhanced TRX1 expression under androgen‐deprived conditions . Elevated TRX1 expression may be the consequence of accumulated ROS generated by cancer cells after exposure to antineoplastic agents .…”

“…Elevated TRX1 expression may be the consequence of accumulated ROS generated by cancer cells after exposure to antineoplastic agents . However, TRX1 itself may not always have oncogenic functions . To date, the role of TRX1 expression in bladder cancer remains to be elucidated.…”

Targeting Thioredoxin System with an Organosulfur Compound, Diallyl Trisulfide (DATS), Attenuates Progression and Metastasis of Triple-Negative Breast Cancer (TNBC)

“…Overexpression of Trx-1 in tumor cells results in the inhibition of apoptosis signal-regulating kinase 1 (ASK1), modulating JNK/p38 signaling pathway and suppressing tumor cell apoptosis [22,23].…”