Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital, Chongqing, 404100, China.
Biochem Biophys Res Commun. 2019 Jan 8;508(2):620-625. doi: 10.1016/j.bbrc.2018.11.062. Epub 2018 Dec 3.
Castration-resistant prostate cancer (CRPC) lacks effective treatment, and studies have shown that PARPi inhibitors, such as Olaparib, are somewhat effective; however, the efficacy of Olaparib in CRPC still needs to be further improved. Nitrogen permease regulator-like 2 (NPRL2) is reported to be a tumor suppressor candidate gene and is closely related to the DNA repair pathway, which can affect the sensitivity of many chemotherapeutic drugs. However, there is no research on whether NPRL2 is associated with sensitivity to Olaparib. Hence, in the present study, we examined the NPRL2 expression levels in several PCa cell lines (LNCaP, PC3, and enzalutamide-resistant LNCaP, named LNPER) by Western blot. In addition, we investigated the role of NPRL2 expression and silencing in cell proliferation and in the regulation of ataxia telangiectasia mutated (ATM), which can mediate DNA repair and sensitivity to Olaparib. Furthermore, we performed in vitro and in vivo experiments to determine the mechanism of action of NPRL2 in adjusting Olaparib sensitivity. Our findings demonstrated that the NPRL2 expression level was upregulated in PCa cells, especially CRPC cells. NPRL2 overexpression promoted growth and resistance to Olaparib, and NPRL2 silencing inhibited proliferation, enhanced sensitivity to Olaparib, and increased CRRL2 expression in PCa cells. In addition, the Olaparib-induced growth delay in NPRL2-silenced PC3 tumors in mice correlated with ATM signaling downregulation, an apoptosis increase and migration/invasion suppression. Our results indicate that NPRL2 silencing enhances sensitivity to Olaparib treatment in CRPC and that NPRL2 may serve as a potential therapeutic target and predict resistance to Olaparib in CRPC.
去势抵抗性前列腺癌（CRPC）缺乏有效治疗方法，研究表明 PARPi 抑制剂，如奥拉帕利，具有一定疗效；然而，奥拉帕利在 CRPC 中的疗效仍需进一步提高。氮渗透酶调节因子样 2（NPRL2）被报道为候选肿瘤抑制基因，与 DNA 修复途径密切相关，可影响多种化疗药物的敏感性。然而，目前尚无研究探讨 NPRL2 是否与奥拉帕利的敏感性相关。因此，在本研究中，我们通过 Western blot 检测了几种前列腺癌细胞系（LNCaP、PC3 和恩扎卢胺耐药的 LNCaP，命名为 LNPER）中 NPRL2 的表达水平。此外，我们研究了 NPRL2 表达和沉默对细胞增殖的作用，以及 ATM（可介导 DNA 修复和对奥拉帕利的敏感性）的调控作用。此外，我们进行了体外和体内实验，以确定 NPRL2 调节奥拉帕利敏感性的作用机制。我们的研究结果表明，NPRL2 在前列腺癌细胞中表达上调，特别是在 CRPC 细胞中。NPRL2 的过表达促进了生长和对奥拉帕利的耐药性，而 NPRL2 的沉默抑制了增殖，增强了对奥拉帕利的敏感性，并增加了前列腺癌细胞中 CRRL2 的表达。此外，在小鼠中，NPRL2 沉默的 PC3 肿瘤中奥拉帕利诱导的生长延迟与 ATM 信号下调、凋亡增加和迁移/侵袭抑制相关。我们的研究结果表明，NPRL2 沉默增强了 CRPC 对奥拉帕利治疗的敏感性，NPRL2 可能成为治疗 CRPC 的潜在靶点，并预测对奥拉帕利的耐药性。
