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<p>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.</p><p></p>

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OPRK1 drives SLC9A3R1 progression to neuroendocrine prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月7日

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  • Linghui Liang,
  • Zhiyi Shen,
  • Yuwei Zhang,
  • Yifei Cheng,
  • Bing Yao,
  • Ninghan Feng,
  • Ruizhe Zhao

摘要

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.