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

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

  • Cancer Lett. 2022 Sep 1;543:215783. doi: 10.1016/j.canlet.2022.215783.
Bonan Chen 1,  Yue Song 2,  Yujuan Zhan 2,  Shikun Zhou 3,  Junzi Ke 4,  Weizhen Ao 4,  Yigan Zhang 5,  Qiqi Liang 6,  Minhui He 6,  Shuhui Li 6,  Fuda Xie 6,  Haonan Huang 6,  Wai Nok Chan 7,  Alvin H K Cheung 7,  Brigette B Y Ma 8,  Wei Kang 7,  Ka Fai To 9,  Jianyong Xiao 10
Affiliations

Affiliations

  • 1 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Research Center of Integrative Medicine, School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; 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.
  • 2 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Research Center of Integrative Medicine, School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China.
  • 3 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Research Center of Integrative Medicine, School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, PR China.
  • 4 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Research Center of Integrative Medicine, School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; iHuman Institute, School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, PR China.
  • 5 The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, PR China.
  • 6 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China.
  • 7 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.
  • 8 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.
  • 9 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. Electronic address: [email protected].
  • 10 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China; Research Center of Integrative Medicine, School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China. Electronic address: [email protected].
PMID: 35700820 DOI: 10.1016/j.canlet.2022.215783
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.

Keywords

Cytosolic ROS; Fangchinoline; NOX4; Non-small cell lung cancer.

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