YC-1 potentiates the antitumor activity of gefitinib by inhibiting HIF-1α and promoting the endocytic trafficking and degradation of EGFR in gefitinib-resistant non-small-cell lung cancer cells
YC-1 potentiates the antitumor activity of gefitinib by inhibiting HIF-1α and promoting the endocytic trafficking and degradation of EGFR in gefitinib-resistant non-small-cell lung cancer cells
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YC-1 通过抑制 HIF-1α 并促进吉非替尼耐药的非小细胞肺癌细胞中 EGFR 的内吞运输和降解来增强吉非替尼的抗肿瘤活性。
DOI：
10.1016/j.ejphar.2020.172961
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发表时间：
2020-05-05
影响因子：
5
通讯作者：
Mou, Ling-Yun
中科院分区：
文献类型：
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作者：
Hu, Hui;Miao, Xiao-Kang;Mou, Ling-Yun
酪氨酸激酶抑制剂（TKI）吉非替尼对EGFR激活敏感突变的NSCLC患者具有良好的治疗效果。然而，大多数患者在治疗6-12个月后最终会因耐药性的产生而复发。在这里，我们发现 HIF-1a 抑制剂 YC-1 通过促进一组具有野生型或突变 EGFR 的人类 NSCLC 细胞中的 EGFR 降解来增强吉非替尼的抗肿瘤功效。 YC-1单独对NSCLC细胞存活影响不大，但显着增强吉非替尼的抗生长和促凋亡作用。在不敏感的NSCLC细胞系中，吉非替尼有效抑制EGFR的磷酸化，但不抑制ERK、AKT和STAT3的下游信号传导；然而，当与 YC-1 治疗相结合时，这些信号通路受到严重损害。吉非替尼治疗诱导 EGFR 在早期内体中停滞，而 YC-1 治疗则促进 EGFR 延迟转运至晚期内体以及受体降解。此外，YC-1 诱导的 HIF-1 α 蛋白减少与 EGFR 降解的增强有关。 HIF-1 α敲低促进 EGFR 降解，显示出与 NSCLC 细胞中吉非替尼和 YC-1 联合治疗相似的协同抗生长和促凋亡作用。我们的研究结果提供了一种新的吉非替尼和 YC-1 联合治疗策略，以扩大吉非替尼的使用并克服 NSCLC 患者对吉非替尼的耐药性。
The tyrosine kinase inhibitor (TKI) gefitinib exerts good therapeutic effect on NSCLC patients with sensitive EGFR-activating mutations. However, most patients ultimately relapse due to the development of drug resistance after 6-12 months of treatment. Here, we showed that a HIF-1 a inhibitor, YC-1, potentiated the antitumor efficacy of gefitinib by promoting EGFR degradation in a panel of human NSCLC cells with wild-type or mutant EGFRs. YC-1 alone had little effect on NSCLC cell survival but significantly enhanced the antigrowth and proapoptotic effects of gefitinib. In insensitive NSCLC cell lines, gefitinib efficiently inhibited the phosphorylation of EGFR but not the downstream signaling of ERK, AKT and STAT3; however, when combined with YC-1 treatment, these signaling pathways were strongly impaired. Gefitinib treatment induced EGFR arrest in the early endosome, and YC-1 treatment promoted delayed EGFR transport into the late endosome as well as receptor degradation. Moreover, the YC-1-induced reduction of HIF-1 alpha protein was associated with the enhancement of EGFR degradation. HIF-1 alpha knockdown promoted EGFR degradation, showing synergistic antigrowth and proapoptotic effects similar to those of the gefitinib and YC-1 combination treatment in NSCLC cells. Our findings provide a novel combination treatment strategy with gefitinib and YC-1 to extend the usage of gefitinib and overcome gefitinib resistance in NSCLC patients.