Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Rehabilitation, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Exp Cell Res. 2020 May 15;390(2):111981. doi: 10.1016/j.yexcr.2020.111981. Epub 2020 Mar 28.
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.
基于多西紫杉醇的化疗被推荐用于转移性去势抵抗性前列腺癌（mCRPC）。然而，化疗耐药性是不可避免的，并且在几轮化疗后最终会进展。因此，探索有助于化疗耐药性的新的治疗靶点和分子机制仍然是必要的。我们之前的研究偶然表明，氮渗透调节因子样 2（NPRL2）的表达上调，NPRL2 被定义为肿瘤抑制因子，与前列腺癌（PCa）和不良预后相关，特别是在 CRPC 中。本研究旨在探讨 NPRL2 在耐药性 CRPC 细胞中的作用。我们发现，NPRL2 在多西紫杉醇耐药性 CRPC 细胞中显著过表达，同时自噬增强，mTOR 信号被抑制。抑制 NPRL2 增加了多西紫杉醇耐药性 CRPC 细胞对多西紫杉醇的敏感性，增强了细胞凋亡并抑制了自噬，而当向 NPRL2 沉默的细胞中添加 mTOR 抑制剂 torin 1 时，则观察到相反的趋势。我们进一步发现，沉默 NPRL2 的多西紫杉醇耐药性 CRPC 细胞对多西紫杉醇在体内敏感。简而言之，我们的研究表明，NPRL2 的过表达通过调节 mTOR 信号通路促进自噬从而促进 CRPC 细胞的化疗耐药性，并抑制细胞凋亡。
