The 3p21.3 tumor suppressor NPRL2 plays an important role in cisplatin-induced resistance in human non-small-cell lung cancer cells
The 3p21.3 tumor suppressor NPRL2 plays an important role in cisplatin-induced resistance in human non-small-cell lung cancer cells
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DOI：
10.1158/0008-5472.can-06-1483
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发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Ji, Lin
中科院分区：
文献类型：
--
作者：
Ueda, Kentaro;Kawashima, Hiroyuki;Ji, Lin
NPRL 2是在人类染色体3p21.3区域发现的新的候选肿瘤抑制基因之一。NPRL 2已在体外和体内显示出有效的肿瘤抑制活性，并已被认为参与DNA错配修复、细胞周期检查点信号传导和细胞凋亡途径的调节。在本研究中，我们分析了40个非小细胞肺癌细胞系中NPRL 2蛋白的内源性表达和细胞对顺铂的反应，发现NPRL 2的表达与顺铂敏感性显著相关，斯皮尔曼相关系数为-0.677（P < 0.00001）。NPRL 2通过N-[1-（2，3-二油酰氧基）丙基]-NNN-三甲基铵甲基硫酸盐：胆固醇纳米颗粒介导的基因转移显著地使对顺铂的反应再敏感，产生40%的肿瘤细胞活力的更大抑制，并导致通过激活NPRL 2中的多个半胱天冬酶诱导的凋亡增加2- 3倍。转染的细胞与未转染的细胞在相同剂量的顺铂下进行比较。此外，在人H322肺癌原位小鼠模型中用NPRL 2纳米颗粒和顺铂的组合进行全身治疗显著增强了顺铂的治疗功效并克服了顺铂诱导的耐药性（P < 0.005）。这些发现暗示了NPRL 2作为预测肺癌患者顺铂反应的生物标志物和作为增强顺铂治疗反应和使对顺铂治疗无反应者再敏感的分子治疗剂的潜力。
NPRL2 is one of the novel candidate tumor suppressor genes identified in the human chromosome 3p21.3 region. The NPRL2 has shown potent tumor suppression activity in vitro and in vivo and has been suggested to he involved in DNA mismatch repair, cell cycle checkpoint signaling, and regulation of the apoptotic pathway. In this study, we analyzed the endogenous expression of the NPRL2 protein and the cellular response to cisplatin in 40 non-small-cell lung cancer cell lines and found that expression of NPRL2 was significantly and reciprocally correlated to cisplatin sensitivity, with a Spearman correlation coefficient of -0.677 (P < 0.00001). Exogenously introduced expression of NPRL2 by N-[1-(2,3-dioleoyloxyl)propyl]-NNN-trimethylammoniummethyl sulfate: cholesterol nanoparticle-mediated gene transfer significantly resensitized the response to cisplatin, yielding a 40% greater inhibition of tumor cell viability and resulting in a 2- to 3-fold increase in induction of apoptosis by activation of multiple caspases in NPRL2-transfected cells compared with untransfected cells at an equal dose of cisplatin. Furthermore, a systemic treatment with a combination of NPRL2 nano-particles and cisplatin in a human H322 lung cancer orthotopic mouse model significantly enhanced the therapeutic efficacy of cisplatin and overcame cisplatin-induced resistance (P < 0.005). These findings implicate the potential of NPRL2 as a biomarker for predicting cisplatin response in lung cancer patients and as a molecular therapeutic agent for enhancing response and resensitizing nonresponders to cisplatin treatment.