159 - The ROS duality in castration-resistant prostate cancer emergence and progression

Abstract

Castration-resistant prostate cancer (CRPC) arises from a failure of standard-of-care androgen deprivation (AD) therapy to suppress emergence of castration-resistant variants from the original AD-responsive prostate cancer (ADPC). Identification of molecular drivers of AD-resistance and CRPC emergence is critical for developing curative therapies. Comparative transcriptomic analysis of parental ADPC cells and their acutely-emergent CRPC counterparts, developed in our laboratory, identified two distinct and novel redox-regulated pathways in mediating castration resistance. The redox-protective protein thioredoxin-1 (TRX1) was elevated under AD in CRPC cells, but not ADPC cells. TRX1 inhibition, via shRNA or the Phase-I approved TRX1 inhibitor PX-12 (not tested in prostate cancer), elevated ROS levels and induced cell death in androgen-deprived CRPC cells and reduced xenograft tumor formation in castrate in vivo models. Unexpectedly, TRX1 inhibition also elevated androgen receptor (AR) levels under AD, and AR depletion mitigated both TRX1 inhibition-mediated ROS production and loss of viability. Our results suggest maintaining AR expression in CRPC induces oxidative stress that requires redox-protective adaptations (such as elevated TRX1) to avoid AD-induced cell death. In contrast to TRX1, we found GC1a, the main subunit of the nitric oxide receptor, soluble guanylate cyclase (sGC), was decreased in CRPC relative to ADPC. Treatment with sGC agonists, including an FDA-approved anti-hypertensive agent, led to reduction in castrate-resistant tumor burden in xenograft models. Tumor suppression was significantly correlated to the extent by which sGC signaling was stimulated in the treated animals. Our preliminary findings indicate sGC signaling is inhibitory to CRPC and that oxidation of the sGC complex is likely to be an important mechanism of signal dampening in CRPC. Our research points to a ROS duality in CRPC, comprising oxidation-mediated inhibition of anti-tumor signaling alongside a concomitant vulnerability to oxidative stress, requiring enhanced redox-protective mechanisms that could serve as novel avenues for therapeutic intervention in CRPC.