# 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.

## Key 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.