Autophagy regulates vinorelbine sensitivity due to continued Keap1-mediated ROS generation in lung adenocarcinoma cells.
Autophagy regulates vinorelbine sensitivity due to continued Keap1-mediated ROS generation in lung adenocarcinoma cells.
复制标题
DOI：
10.1038/s41420-018-0098-6
复制
发表时间：
2018
影响因子：
7
通讯作者：
Chiu WH
中科院分区：
文献类型：
--
作者：
Wu YW;Lin CF;Lin YS;Su WC;Chiu WH
自噬是转移性癌症因饥饿、缺氧、代谢应激、化疗和放疗而避免死亡的诱导机制之一。一些文献表明，化疗联合自噬抑制剂可以克服耐药性。我们对PTEN过表达、mTOR敲低、Keap1敲低的AS2细胞进行了修饰，对PTEN敲低、Atg5敲低、Keap1过表达的A549细胞进行了修饰。我们的研究旨在探索自噬如何调节Keap1、ROS的产生以及长春瑞滨诱导的这些细胞系的凋亡。我们发现肺癌PC14PE6/AS2 （AS2）的mTOR和Akt表达高于A549细胞，PTEN表达低于A549细胞。与A549细胞相比，AS2细胞的自噬下降，p62积累和LC3 II转化减少。A549细胞的Keap1/Nrf2活性低于AS2细胞，抗氧化反应元件（ARE）活性高于AS2细胞。我们对PTEN过表达、mTOR敲低、Keap1敲低的AS2细胞进行修饰，发现p62和LC3表达扩增，同时Akt、Keap1、ROS和vinorelbinin诱导的细胞凋亡减少。p62、LC3表达下降，Akt、Keap1、ROS和vinorelbinin诱导的A549细胞凋亡增加，PTEN敲低、Atg5敲低、Keap1过表达。Keap1过表达降低了A549细胞的ARE水平，而在Keap1过表达的AS2细胞中ARE水平呈上升趋势。自噬抑制剂使A549和CL1-5细胞产生更多ROS，并引起vinorelbinine诱导的细胞凋亡。根据这些发现，自噬通过在肺腺癌细胞中持续keap1介导的ROS生成来调节维诺瑞滨敏感性。化疗联合自噬抑制剂克服耐药需要更多的证据证明。该初步研究证实了肺腺癌细胞的vnr敏感策略，通过自噬调控因子调节keap1介导的ROS生成和vnr诱导的细胞凋亡。
Autophagy is one of the induced mechanisms in metastatic cancer to escape death due to starvation, hypoxia, metabolic stresses, chemotherapy, and radiation. Some publications have revealed that chemotherapy combined with autophagy inhibitor will overcome drug resistance. We modified AS2 cells with PTEN overexpression, mTOR knockdown, or Keap1 knockdown, and made modification of A549 cells with PTEN knockdown, Atg5 knockdown, and Keap1 overexpression. Our study was aimed toward an exploration of how autophagy modulates Keap1, ROS generation, and vinorelbine-induced apoptosis in these cell lines. We found that lung cancer PC14PE6/AS2 (AS2) had higher mTOR and Akt and also lower PTEN expression than A549 cells. Descended autophagy was demonstrated with more decreased p62 accumulation and LC3 II conversion in AS2 cells as compared to A549 cells. The A549 cells had lower Keap1/Nrf2 and more active anti-oxidant response element (ARE) activity than the AS2 cells. We modified AS2 cells with PTEN overexpression, mTOR knockdown, Keap1 knockdown, and revealed amplified p62 and LC3 expression accompanied with decreased Akt, Keap1, ROS, and vinorelbine-induced apoptosis. Declined p62, LC3 expression were accompanied with increased Akt, Keap1, ROS, and vinorelbine-induced apoptosis after modification of A549 cells with PTEN knockdown, Atg5 knockdown, and Keap1 overexpression. Keap1 overexpression lowered ARE levels in A549 cells, and ARE level exhibited up-growth in Keap1 knockdown AS2 cells. The autophagy inhibitor caused more ROS generation and vinorelbine-induced apoptosis in the A549 and CL1-5 cells. According to these findings, autophagy regulates vinorelbine sensitivity by continuing Keap1-mediated ROS generation in lung adenocarcinoma cells. It needs more evidence to prove that chemotherapy combined with autophagy inhibitor will overcome drug resistance. The pilot study demonstrated a VNR-sensitive strategy in lung adenocarcinoma cells, by which regulators of autophagy modulated Keap1-mediated ROS generation and VNR-induced apoptosis.
登录
查看更多内容
自噬在低氧条件下有助于非小细胞肺癌的化学抗性。
影响因子：
5.8
作者：
Lee JG;Shin JH;Shim HS;Lee CY;Kim DJ;Kim YS;Chung KY
通讯作者：
Chung KY
影响因子：
3.3
作者：
Marsit, CJ;Zheng, SC;Kelsey, KT
通讯作者：
Kelsey, KT
影响因子：
4.8
作者：
Noda, T;Ohsumi, Y
通讯作者：
Ohsumi, Y
影响因子：
3.7
作者：
Errafiy R;Aguado C;Ghislat G;Esteve JM;Gil A;Loutfi M;Knecht E
通讯作者：
Knecht E
DOI：
10.1074/jbc.m109.096545
发表时间：
2010-05-28
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Copple IM;Lister A;Obeng AD;Kitteringham NR;Jenkins RE;Layfield R;Foster BJ;Goldring CE;Park BK
通讯作者：
Park BK