Applied electric fields suppress osimertinib-induced cytotoxicity via inhibiting FOXO3a nuclear translocation through AKT activation
Applied electric fields suppress osimertinib-induced cytotoxicity via inhibiting FOXO3a nuclear translocation through AKT activation
复制标题
施加电场通过 AKT 激活抑制 FOXO3a 核转位，从而抑制奥西替尼诱导的细胞毒性
DOI：
10.1093/carcin/bgz150
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发表时间：
2020-05-01
期刊：
影响因子：
4.7
通讯作者：
He, Yong
中科院分区：
文献类型：
--
作者：
Li, Li;Hu, Chen;He, Yong
奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂，用于治疗T790 M突变型非小细胞肺癌（NSCLC）。奥希替尼获得性耐药是一个日益增长的临床挑战，尚未完全了解。内源性电场（EFs），肿瘤微环境的组成部分，与癌细胞的迁移和增殖。然而，EFs对药物效率的影响尚未研究。在这项研究中，我们观察到EF抵消了奥希替尼的作用。100 mV/mm的EF抑制了奥希替尼诱导的细胞死亡并促进了细胞增殖。转录分析显示，由奥希替尼诱导的表达模式被EFs刺激改变。KEGG分析显示，差异表达基因主要集中在PI 3 K-AKT通路。然后，我们发现奥希替尼抑制AKT磷酸化，而EFs刺激导致AKT的显著活化，这可以覆盖奥希替尼产生的作用。重要的是，LY 294002对PI 3 K/AKT的药理学抑制减弱了EF诱导的AKT活化，并恢复了EF抑制的奥希替尼的细胞毒性，这证明AKT活化对于EF减弱奥希替尼的疗效至关重要。此外，EFs激活AKT导致叉头盒O3 a（FOXO 3a）磷酸化，并减少奥希替尼诱导的FOXO 3a核转位，导致Bim表达降低，奥希替尼的细胞毒性减弱。综上所述，我们证明了EFs通过AKT/FOXO 3a/Bim途径抑制奥希替尼的抗肿瘤活性，并且PI 3 K/AKT抑制剂与奥希替尼联合使用抵消了EFs的作用。我们的研究结果为提高奥希替尼在NSCLC患者中的疗效的治疗策略提供了初步数据。
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor against T790M-mutant non-small cell lung cancer (NSCLC). Acquired resistance to osimertinib is a growing clinical challenge that is not fully understood. Endogenous electric fields (EFs), components of the tumor microenvironment, are associated with cancer cell migration and proliferation. However, the impact of EFs on drug efficiency has not been studied. In this study, we observed that EFs counteracted the effects of osimertinib. EFs of 100 mV/mm suppressed osimertinib-induced cell death and promoted cell proliferation. Transcriptional analysis revealed that the expression pattern induced by osimertinib was altered by EFs stimulation. KEGG analysis showed that differential expression genes were mostly enriched in PI3K-AKT pathway. Then, we found that osimertinib inhibited AKT phosphorylation, while EFs stimulation resulted in significant activation of AKT, which could override the effects generated by osimertinib. Importantly, pharmacological inhibition of PI3K/AKT by LY294002 diminished EF-induced activation of AKT and restored the cytotoxicity of osimertinib suppressed by EFs, which proved that AKT activation was essential for EFs to attenuate the efficacy of osimertinib. Furthermore, activation of AKT by EFs led to phosphorylation of forkhead box O3a (FOXO3a), and reduction in nuclear translocation of FOXO3a induced by osimertinib, resulting in decreased expression of Bim and attenuated cytotoxicity of osimertinib. Taken together, we demonstrated that EFs suppressed the antitumor activity of osimertinib through AKT/FOXO3a/Bim pathway, and combination of PI3K/AKT inhibitor with osimertinib counteracted the effects of EFs. Our findings provided preliminary data for therapeutic strategies to enhance osimertinib efficacy in NSCLC patients.