Docetaxel-based chemotherapy is recommended for metastatic castration-resistant prostate cancer (mCRPC). However, chemoresistance is inevitable and eventually progresses after several rounds of chemotherapy. Therefore, exploration of new therapeutic targets and molecular mechanisms that contribute to chemoresistance remains necessary. Our previous study accidentally demonstrated that expression of nitrogen permease regulator-like 2 (NPRL2), which is defined as a tumor suppressor, is upregulated in prostate cancer (PCa) and linked to poor prognosis, particularly in CRPC. The aim of this study was to investigate the role of NPRL2 in the chemoresistant CRPC cells. We found that NPRL2 was significantly overexpressed in docetaxel-resistant CRPC cells, while autophagy was enhanced and mTOR signaling was inhibited. Inhibiting NPRL2 increased the sensitivity to docetaxel in docetaxel-resistant CRPC cells, enhanced apoptosis and inhibited autophagy, and the opposite trends were observed when the mTOR inhibitor torin 1 was added to NPRL2-silenced cells. We further found that NPRL2 silenced docetaxel-resistant CRPC cells were sensitive to docetaxel in vivo. Briefly, our research reveals that overexpression of NPRL2 promotes chemoresistance by regulating autophagy via mTOR signaling and inhibits apoptosis in CRPC cells.

中文翻译：

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NPRL2通过调节mTOR途径的自噬，促进去势抵抗性前列腺癌细胞中的多西他赛化学耐药性。

建议以多西他赛为基础的化疗用于转移性去势抵抗性前列腺癌（mCRPC）。然而，化学抗性是不可避免的，并在数轮化疗后最终发展。因此，有必要探索有助于化学抗性的新治疗靶标和分子机制。我们先前的研究意外地证明，被定义为肿瘤抑制因子的氮透酶调节剂样2（NPRL2）的表达在前列腺癌（PCa）中上调，并且与不良预后有关，尤其是在CRPC中。这项研究的目的是调查NPRL2在化学耐药性CRPC细胞中的作用。我们发现，NPRL2在耐多西他赛的CRPC细胞中明显过表达，而自噬得到增强并且mTOR信号被抑制。在耐多西他赛的CRPC细胞中，抑制NPRL2可提高对多西他赛的敏感性，增强细胞凋亡并抑制自噬，当将mTOR抑制剂torin 1加入NPRL2沉默的细胞中时，观察到相反的趋势。我们进一步发现，NPRL2沉默多西他赛耐药的CRPC细胞在体内对多西他赛敏感。简而言之，我们的研究揭示了NPRL2的过表达通过mTOR信号传导调节自噬并促进CRPC细胞凋亡，从而促进了化学抗性。