Inhibition of autophagy by YC-1 promotes gefitinib induced apoptosis by targeting FOXO1 in gefitinib-resistant NSCLC cells
Inhibition of autophagy by YC-1 promotes gefitinib induced apoptosis by targeting FOXO1 in gefitinib-resistant NSCLC cells
复制标题
YC-1 对自噬的抑制通过靶向吉非替尼耐药 NSCLC 细胞中的 FOXO1 来促进吉非替尼诱导的细胞凋亡。
DOI：
10.1016/j.ejphar.2021.174346
复制
发表时间：
2021-07-17
影响因子：
5
通讯作者：
Mou, Ling-Yun
中科院分区：
文献类型：
--
作者：
Hu, Hui;Zhang, Xiao-Wei;Mou, Ling-Yun
非小细胞肺癌（NSCLC）是世界上最常见的癌症。吉非替尼是一种EGFR酪氨酸激酶抑制剂，可高效治疗携带EGFR激活突变（L 858 R或Ex 19 del）的NSCLC患者。然而，尽管吉非替尼治疗具有良好的疾病控制，但先天性耐药和不可避免的获得性耐药代表了NSCLC治疗的巨大挑战。吉非替尼有效诱导细胞保护性自噬，这已被暗示有助于NSCLC细胞对吉非替尼的先天性和获得性耐药性。目前，消除自噬被认为是NSCLC治疗的一种有前途的策略。在本研究中，首次发现YC-1（一种HIF-1 α抑制剂）通过破坏自噬体和溶酶体的融合，从而增强吉非替尼在吉非替尼耐药NSCLC细胞中的促凋亡作用，从而显著抑制吉非替尼诱导的自噬。此外，吉非替尼和YC-1的组合抗自噬和促凋亡作用被证明与叉头盒蛋白O 1（FOXO 1）转录活性的增强相关，这是由吉非替尼耐药NSCLC细胞中p-FOXO 1蛋白水平的增加引起的。我们的数据表明，通过靶向FOXO 1抑制自噬可能是克服对EGFR-TKI的先天性和获得性抗性的可行治疗策略。
Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Gefitinib, an inhibitor of EGFR tyrosine kinase, is highly effective in treating NSCLC patients with activating EGFR mutations (L858R or Ex19del). However, despite excellent disease control with gefitinib therapy, innate resistance and inevitable acquired resistance represent immense challenges in NSCLC therapy. Gefitinib potently induces cytoprotective autophagy, which has been implied to contribute to both innate and acquired resistance to gefitinib in NSCLC cells. Currently, abrogation of autophagy is considered a promising strategy for NSCLC therapy. In the present study, YC-1, an inhibitor of HIF-1 alpha, was first found to significantly inhibit the autophagy induced by gefitinib by disrupting the fusion of autophagosomes and lysosomes and thereby enhancing the proapoptotic effect of gefitinib in gefitinib-resistant NSCLC cells. Furthermore, the combinational anti-autophagic and pro-apoptotic effect of gefitinib and YC-1 was demonstrated to be associated with an enhanced of forkhead box protein O1 (FOXO1) transcriptional activity which resulted from an increase in the p-FOXO1 protein level in gefitinib-resistant NSCLC cells. Our data suggest that inhibition of autophagy by targeting FOXO1 may be a feasible therapeutic strategy to overcome both innate and acquired resistance to EGFR-TKIs.