TXNDC9 regulates oxidative stress-induced androgen receptor signaling to promote prostate cancer progression

Reactive oxygen species (ROS) and ROS-induced oxidative stress are associated with prostate cancer (PCa) development and castrate-resistant tumor progression. This is in part through the activation of the androgen receptor (AR) signaling. However, the molecular underpinning of ROS to activate AR remains poorly understood. Here, we report that the thioredoxin domain-containing 9 (TXNDC9) is an important regulator of ROS to trigger AR signaling. TXNDC9 expression is upregulated by ROS inducer, and increased TXNDC9 expression in patient tumors is associated with advanced clinical stages. TXNDC9 promotes PCa cell survival and proliferation. It is required for AR protein expression and AR transcriptional activity under oxidative stress conditions. Mechanistically, ROS inducers promote TXNDC9 to dissociate from PRDX1, but enhance a protein association with MDM2. Concurrently, PRDX1 enhances its association with AR. These protein interaction exchanges result in not only MDM2 protein degradation, but also PRDX1 mediated AR protein stabilization, and subsequent elevation of AR signaling. Blocking PRDX1 by its inhibitor, Conoidin A (CoA), suppresses AR signaling, PCa cell proliferation, and xenograft tumor growth even under androgen-deprived conditions. These tumor-suppressive effects of CoA were further strengthened when in combination with enzalutamide treatment. Together, these studies demonstrate that the TXNDC9-PRDX1 axis plays an important role for ROS to activate AR functions. It provides a proof-of-principle that co-targeting AR and PRDX1 may be more effective to control PCa growth.