OPRK1 drives SLC9A3R1 progression to neuroendocrine prostate cancer

TL;DR

This study identifies OPRK1 as a key driver in the progression of neuroendocrine prostate cancer, offering new insights for treatment.

Contribution

The study reveals OPRK1's role in treatment-induced neuroendocrine differentiation and proposes it as a novel therapeutic target.

Findings

OPRK1 levels correlate with treatment-induced neuroendocrine differentiation and poor prognosis in prostate cancer.

AR represses OPRK1 transcription, which can be reversed by ARPIs.

OPRK1 activates autophagic degradation of REST via SLC9A3R1, promoting neuroendocrine differentiation.

Abstract

Neuroendocrine differentiation (NED) plays a critical role in endocrine therapy resistance and dismal outcomes among prostate cancer (PCa) patients. The emergence of treatment-induced neuroendocrine prostate cancers (t-NEPCs) with the utilization of second-generation androgen receptor (AR) pathway inhibitors (ARPIs) poses a significant challenge, as the molecular underpinnings remain elusive. Here, our investigation unveils a close correlation between heightened levels of opioid receptor membrane protein OPRK1 and treatment-induced NED (t-NED), alongside an adverse prognosis in PCa cohorts. Our findings illuminate that AR represses OPRK1 transcription by binding to its promoter, a regulation amenable to reversal via ARPI administration. Further exploration reveals that OPRK1 stimulation triggers autophagic degradation of REST upon up-regulation and interaction with SLC9A3R1, thereby instigating NED. In essence, OPRK1 experiences negative control by AR and emerges as a pivotal instigator of t-NED. Combining JTC-801 with CQ successfully impedes NEPC progression by impacting the OPRK1/SLC9A3R1/autophagy/REST axis. Our study accentuates OPRK1 as a novel therapeutic target for PCa management and furnishes profound insights into the pathogenesis of t-NEPC.

Figures