Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) showed great therapeutic efficacy for non-small cell lung cancer (NSCLC) patients. However, acquired resistance severely limits the clinical application and efficacy of EGFR-TKIs. In the current study, we found that solamargine (SM), a natural alkaloid derived from the fruit of Lycium tomato lobelia, has been found to inhibit the progression of NSCLC and enhance the anticancer effect of EGFR-TKIs. In brief, SM significantly inhibited the cell viability of NSCLC cells and enhanced the anticancer effect of gefitinib (GFTN) and erlotinib (ERL). Mechanistically, SM decreased the expression of MALAT1 and induced miR-141-3p, whereas reduced SP1 protein levels. Interestingly, both MALAT1 and Sp1 have classical and conservative binding sites of miR-141-3p in their 3'-UTR regions. Silence of MALAT1 and overexpression of miR-141-3p both decreased the protein expression of Sp1. Subsequently, promoter activity and protein expression of IGFBP1 were upregulated by SM, which was not observed in cells with SP1 overexpression. Moreover, the inhibitory effect of SM on cell growth was significantly blocked by knockdown of IGFBP1 expression. More importantly, the combination of SM and GFTN synergistically inhibited the progression of lung cancer. Similar results were observed in experiments in vivo. Finally, the clinical relevance of MALAT1, Sp1 and IGFBP1 was further validated using bioinformatics analysis. Taken together, we confirmed that SM significantly enhanced the anticancer effect of EGFR-TKIs by regulating the MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway. This study unravels a novel mechanism and suggests a new potential NSCLC-associated therapy.

中文翻译：

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Solamargine 通过调节 MALAT1/miR-141-3p/Sp1/IGFBP1 信号通路增强吉非替尼在非小细胞肺癌中的抗肿瘤作用。

肺癌是全球癌症相关死亡的主要原因。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）对非小细胞肺癌（NSCLC）患者显示出良好的治疗效果。然而，获得性耐药严重限制了EGFR-TKIs的临床应用和疗效。在目前的研究中，我们发现索拉玛吉尼（SM）是一种源自番茄半边莲果实的天然生物碱，已被发现可以抑制NSCLC的进展并增强EGFR-TKIs的抗癌作用。简而言之，SM显着抑制NSCLC细胞的细胞活力，增强吉非替尼（GFTN）和厄洛替尼（ERL）的抗癌作用。从机制上讲，SM 降低了 MALAT1 的表达并诱导 miR-141-3p，同时降低了 SP1 蛋白水平。有趣的是，MALAT1 和 Sp1 在其 3'-UTR 区域均具有 miR-141-3p 的经典且保守的结合位点。MALAT1 的沉默和 miR-141-3p 的过表达都会降低 Sp1 的蛋白表达。随后，SM 上调了 IGFBP1 的启动子活性和蛋白表达，而在 SP1 过表达的细胞中未观察到这种情况。此外，SM对细胞生长的抑制作用被IGFBP1表达的敲低显着阻断。更重要的是，SM和GFTN的组合可以协同抑制肺癌的进展。在体内实验中也观察到类似的结果。最后，利用生物信息学分析进一步验证了 MALAT1、Sp1 和 IGFBP1 的临床相关性。综上所述，我们证实 SM 通过调节 MALAT1/miR-141-3p/Sp1/IGFBP1 信号通路显着增强 EGFR-TKIs 的抗癌作用。这项研究揭示了一种新的机制，并提出了一种新的潜在的 NSCLC 相关疗法。