Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells via IL-6/STAT3 Pathway Inhibition
Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells via IL-6/STAT3 Pathway Inhibition
复制标题
DOI：
10.1248/bpb.b17-00271
复制
发表时间：
2017-08-01
影响因子：
2
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Lou, Wei;Chen, Yan;Wang, Jun
对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的获得性耐药是EGFR突变型非小细胞肺癌（NSCLC）治疗效率的最重要限制因素。许多工作已经将上皮间质转化（EMT）与耐药性的出现联系起来，因此，正在进行的研究一直集中在探索逆转EMT以延缓或预防耐药性的治疗选择。Polyphyllin I（PPI）是从巴黎根茎中分离得到的具有抗癌活性的天然化合物。在目前的工作中，我们的目的是证明PPI是否可以逆转EMT和克服获得性EGFR-TKI耐药。我们将HCC 827肺腺癌细胞暴露于厄洛替尼，导致获得性耐药，具有强烈的EMT特征。PPI有效地恢复了获得性耐药细胞的药物敏感性。PPI逆转了厄洛替尼耐药细胞的EMT，降低了白细胞介素-6/信号转导和转录激活因子3（IL-6/STAT 3）信号通路的激活。此外，加入IL-6部分取消PPI的致敏反应。此外，厄洛替尼和PPI的联合治疗完全消除了异种移植物中的肿瘤生长，这与EMT逆转相关。综上所述，PPI通过调节IL-6/STAT 3信号通路逆转EMT，可作为克服NSCLC EGFR TKI耐药的新方案。PPI和厄洛替尼联合治疗为肺癌患者加强药物反应和延长生存期提供了一个充满希望的未来。
Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.