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Amentoflavone from Ginkgo biloba inhibits EMT-driven lung cancer metastasis by targeting TGFBR2: Integrative network
Kaile Liu1, Kaiting Chen1, Xiaoxue Zhao1
1Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
Ethnopharmacological Relevance:
In non-small cell lung cancer (NSCLC), fatal outcomes predominantly result from metastatic dissemination, highlighting an urgent need for metastasis-directed therapies. Amentoflavone (AMF), a natural biflavonoid found in Ginkgo biloba and other medicinal plants, exhibits known antitumor activity. However, its role in NSCLC metastasis and the underlying mechanisms remain poorly understood.
Aim Of The Study:
This study aimed to investigate the anti-metastatic effects of AMF from Ginkgo biloba in NSCLC and to elucidate the underlying molecular mechanisms.
Materials And Methods:
A network pharmacology approach combined with machine learning was used to predict AMF targets and derive a core diagnostic gene signature. Molecular docking and 100-ns molecular dynamics simulations were performed to characterize AMF-target binding and stability. In vitro, NSCLC cell migration was assessed using wound-healing (scratch) assays and Transwell migration chambers, with mechanistic insights obtained by Western blot analysis of EMT-related proteins. In vivo efficacy was evaluated in a murine pulmonary metastasis model established via tail-vein tumor cell injection. The machine learning model achieved an AUC of 0.951 in the internal testing set and 0.814 in the external validation set (GSE31210), indicating high robustness.
Results:
Convergent computational analyses identified TGFBR2 as a key candidate target of AMF. Docking and 100-ns MD simulations predicted a strong and dynamically stable binding mode of AMF to TGFBR2. In vitro, AMF significantly reduced NSCLC cell migration, accompanied by downregulation of TGFBR2 and inhibition of Smad2/3 phosphorylation, which collectively reversed epithelial-mesenchymal transition (EMT). Consistently, AMF suppressed NSCLC metastasis in vivo by inhibiting the TGF-β/Smad signaling pathway.
Conclusion:
Our data indicate that AMF functions as an anti-metastatic agent in NSCLC at least in part by downregulating TGFBR2, thereby dampening TGF-β/Smad signaling and preventing EMT. These findings highlight AMF as a promising natural candidate for developing anti-metastatic therapies that appear well tolerated under the conditions tested.
Insights
Amentoflavone (AMF) from Ginkgo biloba inhibits non-small cell lung cancer (NSCLC) metastasis by targeting TGFBR2. This natural compound suppresses epithelial-mesenchymal transition (EMT) and dampens TGF-β/Smad signaling, offering a promising anti-metastatic therapy.
Area of Science:
- Oncology
- Pharmacology
- Computational Biology
Background:
- Metastasis in non-small cell lung cancer (NSCLC) is a primary cause of mortality, necessitating novel metastasis-directed therapies.
- Amentoflavone (AMF), a biflavonoid from medicinal plants like Ginkgo biloba, shows antitumor potential, but its anti-metastatic mechanisms in NSCLC are unclear.
Purpose of the Study:
- To investigate the anti-metastatic effects of Amentoflavone (AMF) in NSCLC.
- To elucidate the molecular mechanisms underlying AMF's anti-metastatic activity, focusing on its interaction with key molecular targets.
Main Methods:
- Network pharmacology and machine learning predicted AMF targets and identified a core gene signature.
- Molecular docking and dynamics simulations assessed AMF-TGFBR2 binding.
- In vitro assays (wound-healing, Transwell) and Western blot analyzed cell migration and epithelial-mesenchymal transition (EMT) markers.
- In vivo studies utilized a murine pulmonary metastasis model.
Main Results:
- TGFBR2 was identified as a key target of AMF, with stable binding confirmed by simulations.
- AMF significantly inhibited NSCLC cell migration in vitro.
- AMF treatment downregulated TGFBR2, inhibited Smad2/3 phosphorylation, and reversed EMT.
- In vivo, AMF suppressed NSCLC metastasis by inhibiting the TGF-β/Smad pathway.
Conclusions:
- AMF exhibits anti-metastatic properties in NSCLC by downregulating TGFBR2 and inhibiting the TGF-β/Smad pathway, thereby preventing EMT.
- These findings establish AMF as a potential natural therapeutic agent for NSCLC metastasis.
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