Cordycepin Reverses Cisplatin Resistance in Non-small Cell Lung Cancer by Activating AMPK and Inhibiting AKT Signaling Pathway.
Cordycepin Reverses Cisplatin Resistance in Non-small Cell Lung Cancer by Activating AMPK and Inhibiting AKT Signaling Pathway.
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DOI：
10.3389/fcell.2020.609285
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发表时间：
2020
影响因子：
5.5
通讯作者：
Lin LZ
中科院分区：
文献类型：
--
作者：
Liao XZ;Gao Y;Zhao HW;Zhou M;Chen DL;Tao LT;Guo W;Sun LL;Gu CY;Chen HR;Xiao ZW;Zhang JX;He MF;Lin LZ
顺铂（DDP）是目前治疗肺癌的一线化疗药物。然而，由于非小细胞肺癌（NSCLC）细胞的获得性耐药性，DDP的治疗效果随时间而丧失。近年来，中药虫草素（cordycepin，Cor）在肿瘤治疗中的作用引起了人们的关注。然而，Cor对NSCLC中DDP耐药的影响尚不清楚。本研究旨在观察Cor联合DDP对NSCLC细胞增殖和凋亡的影响，并探讨其可能的机制。观察DDP单独或联合Cor对NSCLC亲代细胞（A549）和DDP耐药细胞（A549 DDP）的增殖和凋亡的影响。采用基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析方法，对A549细胞DDP敏感和耐药的差异基因和信号通路进行了研究。通过Western印迹分析评估MAPK和PI 3 K-AKT信号通路的扰动。我们的数据表明，Cor显着增强DDP对A549和A549 DDP细胞增殖的抑制作用和促进细胞凋亡。与单独DDP相比，协同作用与AMPK的激活; AKT，mTOR和下游P709 S6 K的抑制;以及AKT通路中的S6磷酸化有关。总体而言，Cor和DDP的组合在存在或不存在DDP抗性的情况下在抑制NSCLC细胞增殖和促进凋亡方面具有协同效应。抗肿瘤活性与AMPK的激活和AKT通路的抑制有关，从而增强DDP对NSCLC的抑制。我们的研究结果表明，Cor联合DDP可能是治疗DDP耐药NSCLC的另一种治疗选择。
Cisplatin (DDP) is the first-line chemotherapeutic agent against lung cancer. However, the therapeutic effect of DDP loses over time due to the acquired drug resistance in non-small cell lung cancer (NSCLC) cells. In recent years, the role of the traditional Chinese medicine (TCM) cordycepin (Cor) in cancer treatment has been attracting attention. However, the effects of Cor on DDP resistance in NSCLC are unclear. In the present study, we aimed to investigate the effects of Cor in combination with DDP on cell proliferation and apoptosis in NSCLC and explore possible underlying mechanisms. The cell proliferation and apoptosis were analyzed in NSCLC parental (A549) and DDP-resistant (A549DDP) cells treated with DDP alone or in combination with Cor both in vitro and in vivo. Different genes and signaling pathways were investigated between DDP-sensitive and DDP-resistant A549 cells by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The perturbations of the MAPK and PI3K-AKT signaling pathways were evaluated by Western blot analysis. Our data showed that Cor markedly enhanced DDP inhibition on cell proliferation and promotion of apoptosis compared to the DDP-alone group in both A549 and A549DDP cells. The synergic actions were associated with activation of AMPK; inhibition of AKT, mTOR, and downstream P709S6K; and S6 phosphorylation in the AKT pathway compared with DDP alone. Collectively, combination of Cor and DDP has a synergistic effect in inhibiting proliferation and promoting apoptosis of NSCLC cells in the presence or absence of DDP resistance. The antitumor activity is associated with activation of AMPK and inhibition of the AKT pathway to enhance DDP inhibition on NSCLC. Our results suggested that Cor in combination with DDP could be an additional therapeutic option for the treatment of DDP-resistant NSCLC.