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

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...

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Published in:	Cancer letters Vol. 543; p. 215783
Main Authors:	Chen, Bonan, Song, Yue, Zhan, Yujuan, Zhou, Shikun, Ke, Junzi, Ao, Weizhen, Zhang, Yigan, Liang, Qiqi, He, Minhui, Li, Shuhui, Xie, Fuda, Huang, Haonan, Chan, Wai Nok, Cheung, Alvin H.K., Ma, Brigette B.Y., Kang, Wei, To, Ka Fai, Xiao, Jianyong
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier B.V 01-09-2022 Elsevier Limited
Subjects:	AKT protein Antibodies Apoptosis Cell adhesion & migration Cell cycle Cell growth Cell migration Cytosolic ROS Drug sensitivity testing Endothelial cells Enzymes Fangchinoline Genomes Genotype & phenotype Kinases Lung cancer Lung nodules Mesenchyme Metastases Metastasis Mitochondria Mitochondrial DNA NADP Natural products Non-small cell lung cancer Non-small cell lung carcinoma NOX4 NOX4 protein Organoids Oxidative stress Proteins Reactive oxygen species Ribonucleic acid RNA Sensitivity analysis Signal transduction Small cell lung carcinoma Stem cell transplantation Stem cells TOR protein Wound healing Xenografts Beijing China United States > US China Germany NOX4 Cytosolic ROS Fangchinoline Non-small cell lung cancer
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Abstract	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 ρ0 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. [Display omitted] •Fangchinoline reversed EMT to inhibit NSCLC cell invasion and migration.•Fangchinoline decreased NOX4-derived cytosolic ROS to inhibit the Akt-mTOR pathway.•Fangchinoline directly and specifically targeted NOX4.•NOX4 is an ideal druggable target in NSCLC.
AbstractList	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 ρ0 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. 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 ρ0 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. [Display omitted] •Fangchinoline reversed EMT to inhibit NSCLC cell invasion and migration.•Fangchinoline decreased NOX4-derived cytosolic ROS to inhibit the Akt-mTOR pathway.•Fangchinoline directly and specifically targeted NOX4.•NOX4 is an ideal druggable target in NSCLC. 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 ρ 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.
ArticleNumber	215783
Author	Li, Shuhui Xie, Fuda Cheung, Alvin H.K. Huang, Haonan To, Ka Fai Zhang, Yigan Chan, Wai Nok Kang, Wei Ma, Brigette B.Y. Liang, Qiqi Zhan, Yujuan He, Minhui Chen, Bonan Ao, Weizhen Zhou, Shikun Xiao, Jianyong Ke, Junzi Song, Yue
Author_xml	– sequence: 1 givenname: Bonan surname: Chen fullname: Chen, Bonan organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 2 givenname: Yue surname: Song fullname: Song, Yue organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 3 givenname: Yujuan surname: Zhan fullname: Zhan, Yujuan organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 4 givenname: Shikun surname: Zhou fullname: Zhou, Shikun organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 5 givenname: Junzi surname: Ke fullname: Ke, Junzi organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 6 givenname: Weizhen surname: Ao fullname: Ao, Weizhen organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 7 givenname: Yigan surname: Zhang fullname: Zhang, Yigan organization: The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, PR China – sequence: 8 givenname: Qiqi surname: Liang fullname: Liang, Qiqi organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 9 givenname: Minhui surname: He fullname: He, Minhui organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 10 givenname: Shuhui surname: Li fullname: Li, Shuhui organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 11 givenname: Fuda surname: Xie fullname: Xie, Fuda organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 12 givenname: Haonan surname: Huang fullname: Huang, Haonan organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China – sequence: 13 givenname: Wai Nok surname: Chan fullname: Chan, Wai Nok organization: Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China – sequence: 14 givenname: Alvin H.K. surname: Cheung fullname: Cheung, Alvin H.K. organization: Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China – sequence: 15 givenname: Brigette B.Y. surname: Ma fullname: Ma, Brigette B.Y. organization: State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong SAR, PR China – sequence: 16 givenname: Wei surname: Kang fullname: Kang, Wei organization: Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China – sequence: 17 givenname: Ka Fai surname: To fullname: To, Ka Fai email: kfto@cuhk.edu.hk organization: Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China – sequence: 18 givenname: Jianyong surname: Xiao fullname: Xiao, Jianyong email: jianyongxiao@gzucm.edu.cn organization: Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/35700820$$D View this record in MEDLINE/PubMed
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Keywords	NOX4 Cytosolic ROS Fangchinoline Non-small cell lung cancer
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Snippet	Few drugs alleviate non-small cell lung cancer (NSCLC) metastasis effectively. Small molecular screening demonstrated that fangchinoline (Fan) reversed...
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SubjectTerms	AKT protein Antibodies Apoptosis Cell adhesion & migration Cell cycle Cell growth Cell migration Cytosolic ROS Drug sensitivity testing Endothelial cells Enzymes Fangchinoline Genomes Genotype & phenotype Kinases Lung cancer Lung nodules Mesenchyme Metastases Metastasis Mitochondria Mitochondrial DNA NADP Natural products Non-small cell lung cancer Non-small cell lung carcinoma NOX4 NOX4 protein Organoids Oxidative stress Proteins Reactive oxygen species Ribonucleic acid RNA Sensitivity analysis Signal transduction Small cell lung carcinoma Stem cell transplantation Stem cells TOR protein Wound healing Xenografts
Title	Fangchinoline inhibits non-small cell lung cancer metastasis by reversing epithelial-mesenchymal transition and suppressing the cytosolic ROS-related Akt-mTOR signaling pathway
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