ReferenceID 5202
Evodiamine suppresses Notch3 signaling in lung tumorigenesis via direct binding to γ-secretases
Phytomedicine
BACKGROUND: Notch activation requires proteolytic cleavage of the receptor by gamma-secretase protein complex. Inhibition of Notch receptor activation (e.g. Notch3) with gamma-secretase inhibitor is a potential new thera
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- Reference Id
- 5202
- Evidence Id
- 21792
- Core Evidence Id
- 21792
- Source Reference Id
- 3694
- Herb2 Reference Id
- HBREF004491
- Subject Paper Key
- HBIN026264_32045841
- Pubmed Id
- 32045841
- Doi
- 10.1016/j.phymed.2020.153176
- Paper Title
- Evodiamine suppresses Notch3 signaling in lung tumorigenesis via direct binding to γ-secretases
- Paper Abstract
- BACKGROUND: Notch activation requires proteolytic cleavage of the receptor by gamma-secretase protein complex. Inhibition of Notch receptor activation (e.g. Notch3) with gamma-secretase inhibitor is a potential new therapeutic approach for the targeted therapy of non-small cell lung cancer (NSCLC). However, only a few safe and effective gamma-secretase inhibitors have been discovered. Evodiamine (EVO), a compound derived from Euodiae Fructus (Chinese name, Wu-Zhu-Yu), exhibits remarkable anti-NSCLC activities. However, the underlying mechanisms of action have yet to be fully elucidated. PURPOSE: We sought to determine the involvement of Notch3 signaling in the anti-NSCLC effects of EVO, and to explore whether EVO suppressed Notch3 signaling by inhibiting gamma-secretase in cultured A549 and H1299 NSCLC cells and in urethane-induced lung cancer FVB mouse model. METHODS: Cell viability, migration, stemness and cell cycle distribution of EVO were examined by the MTT assay, wound healing assay, soft agar colony assay and flow cytometry analysis, respectively. The binding affinity of EVO and gamma-secretase complex was analyzed by molecular docking. Cellular thermal shift assay (CETSA) was performed to study the drug-target interactions in NSCLC cells. Protein levels were determined by Western blotting. RESULTS: EVO dramatically inhibited cell viability, induced G2/M cell cycle arrest, suppressed cell migration, and reduced stemness in NSCLC cells. Mechanistic studies indicated that EVO prevented the gamma-secretase cleavage of Notch3 at the cell surface and hence inhibited Notch3 activation. Moreover, EVO notably reduced tumor growth in the mouse model and inhibited Notch3 activity in the tumors. CONCLUSION: This study provides new insights into the anti-NSCLC action of EVO, and suggests that suppressing Notch3 signaling by inhibiting gamma-secretase is a mechanism of action underlying the anti-NSCLC effect of EVO.
- Journal
- Phytomedicine
- Publish Year
- 2020
- Experiment Subject
- mouse; cultured a549; h1299 nsclc cells; nsclc cells
- Experiment Type
- Animal Experiment
- Phenotype Related
- Lung Cancer; Tumor; Anti-nsclc; Non-small Cell Lung Cancer; Tumors
- Paper Title Cn
- Paper Title En
- Evodiamine suppresses Notch3 signaling in lung tumorigenesis via direct binding to γ-secretases
- Bilingual Status
- semi_complete