Androgen deprivation therapy (ADT) initially suppresses prostate cancer (PC) progression. However, castration-resistant PC (CRPC) cells inevitably emerge, resulting in incurable disease. We recently demonstrated that AD produces a form of cellular senescence leading to outgrowth of CRPC subpopulations from the AD-sensitive parental cells. Gene expression profiling studies comparing the parental LNCaP line to the senescence-resistant, early CRPC variant, LNCaP SB5, revealed an enrichment of redox-protective proteins in the latter under AD conditions. This finding suggests that redox stress due to hyperactivated mitogenic/survival signaling or metabolic stresses may be an important and understudied Achilles heel in the progression to CRPC. Here we present the effects of inhibiting thioredoxin-1 (TRX1), a redox-protective protein that was identified as being elevated in our early CRPC LNCaP SB5 model as well as in human CRPC vs. AD-responsive PC datasets. Suppression of TRX1 expression via shRNA led to profound growth suppression of CRPC cells, relative to their AD-sensitive counterparts, and significantly reduced CRPC xenograft tumor growth. Furthermore, under AD, TRX1 suppression promoted p53-induced cell death, which was accompanied by increased reactive oxygen species (ROS). Curiously, TRX1 inhibition led to increased AR and Sp1 expression under AD, and the oxidative stress effects associated with TRX1 inhibition could be mitigated by depleting AR expression. These in vitro and in vivo results were recapitulated using PX-12 a phase I-approved pharmacologic TRX1 inhibitor. Thus our results point to TRX1 as a critical requirement for protecting against redox stress evoked by the inappropriate reactivation of AR in a low-androgen environment in CRPC. Our work provides a rationale for using TRX1 inhibitors in conjunction with ADT to limit CRPC.

Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Rolando D.Z. Lyles, Deukwoo Kwon, Yuguang Ban, Steven Xi Chen, Merce Jorda, Kerry Burnstein, Priyamvada Rai. Inappropriate AR reactivation-induced redox stress as a novel therapeutic target in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B032.