Fangchinoline inhibits non-small cell lung cancer metastasis by reversing epithelial-mesenchymal transition and suppressing the cytosolic ROS-related Akt-mTOR signaling pathway

被引:46
|
作者
Chen, Bonan [1 ,2 ,3 ]
Song, Yue [1 ,2 ]
Zhan, Yujuan [1 ,2 ]
Zhou, Shikun [1 ,2 ,4 ]
Ke, Junzi [1 ,2 ,5 ]
Ao, Weizhen [1 ,2 ,5 ]
Zhang, Yigan [6 ]
Liang, Qiqi [1 ]
He, Minhui [1 ]
Li, Shuhui [1 ]
Xie, Fuda [1 ]
Huang, Haonan [1 ]
Chan, Wai Nok [3 ]
Cheung, Alvin H. K. [3 ]
Ma, Brigette B. Y. [7 ]
Kang, Wei [3 ]
To, Ka Fai [3 ]
Xiao, Jianyong [1 ,2 ]
机构
[1] Guangzhou Univ Chinese Med, Dept Biochem, Guangzhou 510006, Peoples R China
[2] Guangzhou Univ Chinese Med, Res Ctr Integrat Med, Sch Basic Med, Guangzhou 510006, Peoples R China
[3] Chinese Univ Hong Kong, Dept Anat & Cellular Pathol, State Key Lab Translat Oncol Inst,Prince Wales Ho, Inst Digest Dis,State Key Lab Digest Dis, Hong Kong, Peoples R China
[4] South China Univ Technol, Sch Biomed Sci & Engn, Guangzhou Int Campus, Guangzhou 511442, Peoples R China
[5] Shanghai Tech Univ, Sch Life Sci & Technol, iHuman Inst, Shanghai 201210, Peoples R China
[6] Lanzhou Univ, Sch Clin Med 1, Lanzhou 730000, Peoples R China
[7] Chinese Univ Hong Kong, State Key Lab Translat Oncol, Sir YK Pao Ctr Canc, Dept Clin Oncol,Hong Kong Canc Inst, Hong Kong, Peoples R China
基金
中国国家自然科学基金;
关键词
Fangchinoline; NOX4; Cytosolic ROS; Non-small cell lung cancer; OXYGEN SPECIES ROS; NADPH OXIDASES; NOX FAMILY; OXIDATIVE STRESS; ACTIVATION; TETRANDRINE; MECHANISMS; EXPRESSION; PROMOTE; BIOLOGY;
D O I
10.1016/j.canlet.2022.215783
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Few drugs alleviate non-small cell lung cancer (NSCLC) metastasis effectively. Small molecular screening demonstrated that fangchinoline (Fan) reversed epithelial-mesenchymal transition (EMT) in NSCLC cells, inhibiting cell invasion and migration. RNA sequencing (RNA-seq) of Fan-treated NSCLC cells revealed that Fan potently quenched the NADP(+) metabolic process. Molecular docking analysis revealed that Fan directly and specifically targeted NOX4. NOX4 was associated with poor prognosis in NSCLC in both The Cancer Genome Atlas (TCGA) and Hong Kong cohorts. In mitochondrial DNA-depleted rho(0) NSCLC cells, Fan decreased cytosolic reactive oxygen species (ROS) to inhibit the Akt-mTOR signaling pathway by directly promoting NOX4 degradation. In TCGA and Hong Kong cohorts, NOX4 upregulation acted as a driver event as it positively correlated with metastasis and oxidative stress. Single-cell RNA-seq indicated that NOX4 was overexpressed, especially in cancer cells, cancer stem cells, and endothelial cells. In mice, Fan significantly impeded subcutaneous xenograft formation and reduced metastatic nodule numbers in mouse lung and liver. Drug sensitivity testing demonstrated that Fan suppressed patient-derived organoid growth dose-dependently. Fan is a potent small molecule for alleviating NSCLC metastasis by directly targeting NOX4 and is a potential novel therapeutic agent.
引用
收藏
页数:15
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