Scutellariabarbata D. Don extraction selectively targets sternness-prone NSCLC cells by attenuating SOX2/SMO/GLI1 network loop
Scutellariabarbata D. Don extraction selectively targets sternness-prone NSCLC cells by attenuating SOX2/SMO/GLI1 network loop
复制标题
黄芩提取物通过减弱 SOX2/SMO/GLI1 网络环路选择性地靶向干细胞倾向的 NSCLC 细胞。
DOI：
10.1016/j.jep.2020.113295
复制
发表时间：
2021-01-30
影响因子：
5.4
通讯作者：
Du, Jing
中科院分区：
文献类型：
--
作者：
Chen, Wei-Wei;Gong, Kai-Kai;Du, Jing
民族药理学相关性：arabarbata D. Don Extraction（SBE）是一种传统中药，临床上已被证明对多种恶性肿瘤有效，其单独或与常规化疗方案联合使用时副作用可耐受。本研究的目的：肿瘤多药耐药是由于肿瘤干细胞的存在，这些细胞具有异常高的Sonic Hedgehog（SHH）级联反应。我们的前期研究表明，SBE通过下调SHH通路对非小细胞肺癌（NSCLC）细胞顺铂（DDP）敏感。然而，SBE是否可以抑制肿瘤干细胞的增殖及其潜在的分子机制仍有待研究。本文进一步探讨了SBE对NSCLC细胞干细胞相关表型的干预作用及其可能的作用机制。材料和方法：采用CCK-8和克隆形成检测法检测SBE对NSCLC和正常上皮细胞的抗增殖作用。球体形成试验和RQ-PCR用于检测SBE孵育后癌症干细胞的增殖和相关标志物表达。在机理上，利用DARTS-WB和SPR揭示了SBE的结合靶点。免疫缺陷小鼠植入患者来源的肿瘤块在体内验证SBE的抗癌effects.Results：SBE选择性地衰减非小细胞肺癌细胞的增殖和干细胞样表型，而不是支气管正常上皮细胞。药物-蛋白相互作用分析表明，SBE可直接与干细胞特异性转录因子性别决定区Y-box 2（SOX 2）结合，干扰SOX 2/SMO/GLI 1正环。结论：SBE通过靶向SOX 2抑制NSCLC细胞的干细胞相关特征，可能成为临床治疗NSCLC的一种新的选择。
Ethnopharmacological relevance: Scutellariabarbata D. Don extraction (SBE), a traditional Chinese medicine, has been proved effective against various malignant disorders in clinics with tolerable side-effects when administered alone or in combination with conventional chemotherapeutic regimens.Aim of this study: Multi-drug resistance of cancer is attributed to existence of cancer stemness-prone cells that harbor aberrantly high activation of Sonic Hedgehog (SHH) cascade. Our previous study has demonstrated that SBE sensitized non-small cell lung cancer (NSCLC) cells to Cisplatin (DDP) treatment by downregulating SHH pathway. Yet, whether SBE could prohibit proliferation of cancer stemness-prone cells and its underlying molecular mechanisms remain to be investigated. In this article, we further investigated intervention of SBE on NSCLC cell stemness-associated phenotypes and its potential mode of action.Materials and methods: CCK-8 and clonal formation detection were used to measure the anti-proliferative potency of SBE against NSCLC and normal epithelial cells. Sphere formation assay and RQ-PCR were used to detect proliferation of cancer stemness cells and associated marker expression upon SBE incubation. Mechanistically, DARTS-WB and SPR were used to unveil binding target of SBE. Immunodeficient mice were implanted with patient derived tumor bulk for in vivo validation of anti-cancer effect of SBE.Results: SBE selectively attenuated proliferation and stemness-like phenotypes of NSCLC cells rather than bronchial normal epithelial cells. Drug-protein interaction analysis revealed that SBE could directly bind with stem cell-specific transcription factor sex determining region Y-box 2 (SOX2) and interfere with the SOX2/SMO/GLI1 positive loop. In vivo assay using patient-derived xenografts (PDXs) model further proved that SBE diminished tumor growth and SOX2 expression in vivo.Conclusion: Our data indicate that SBE represses stemness-related features of NSCLC cells via targeting SOX2 and may serve as an alternative therapeutic option for clinic treatment.