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Licoflavone A Suppresses Gastric Cancer Growth and Metastasis by Blocking the VEGFR-2 Signaling Pathway
Gong Hongxia1,2,3,4, Jin Xiaojie1,5, Leng Guangxian6
1Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000 Gansu, China.
Objectives:
Licoflavone A (LA) is a natural flavonoid compound derived from the root of Glycyrrhiza. This study investigated the antitumor effect and underlying molecular mechanisms of LA against gastric cancer (GC) in vitro and in vivo.
Materials And Methods:
A CCK8 assay was used to measure the antiproliferative activity of LA in human GC SGC-7901, MKN-45, MGC-803 cells, and human GES-1 cells. Target prediction and protein-protein interaction (PPI) analysis were used to identify the potential molecular targets of LA. The binding pattern of LA to VEGFR-2 was analyzed by molecular docking and molecular dynamic (MD). The affinity of LA for VEGFR-2 was determined by microscale thermophoresis (MST). The protein tyrosine kinase activity of VEGFR-2 in the presence of LA was determined by an enzyme activity test. The effect of LA on the proliferation of VEGF-stimulated MKN-45 cells was measured with CCK8 assays, clone formation assays, and 3D microsphere models. Hoechst 33342 staining, FCM, MMP, and WB assays were used to investigate the ability of LA to block cell cycle and promote apoptosis of VEGF-stimulated MKN-45 cells. Transwell matrix assays were used to measure migration and invasion, and WB assays were used to measure EMT.
Results:
LA inhibited the proliferation of SGC-7901, MKN-45, and MGC-803 cells and VEGF-stimulated MKN-45 cells. VEGFR-2 was identified as the target of LA. LA could also block cell cycle, induce apoptosis, and inhibit migration, invasion, and EMT of VEGF-stimulated MKN-45 cells. Functional analyses further revealed that the cytotoxic effect of LA on VEGF-stimulated MKN-45 cells potentially involved the PI3K/AKT and MEK/ERK signaling pathways.
Conclusions:
This study demonstrates that LA has anti-GC potency in vitro and in vivo. LA affects the proliferation, cycle, apoptosis, migration, invasion, and EMT by targeting VEGFR-2 and blocks the PI3K/AKT and MEK/ERK signaling pathways in VEGF-stimulated MKN-45 cells.
Insights
Licoflavone A (LA) exhibits potent antitumor effects against gastric cancer (GC) by inhibiting cell proliferation and inducing apoptosis. This natural flavonoid targets VEGFR-2, impacting key signaling pathways involved in GC progression.
Area of Science:
- Natural product chemistry
- Molecular oncology
- Cancer biology
Background:
- Gastric cancer (GC) remains a significant global health challenge with limited effective treatments.
- Natural compounds offer potential therapeutic avenues for cancer, warranting investigation into their mechanisms.
- Licoflavone A (LA), a flavonoid from Glycyrrhiza, has shown promise but requires detailed mechanistic studies in GC.
Purpose of the Study:
- To investigate the antitumor efficacy of Licoflavone A (LA) against gastric cancer (GC).
- To elucidate the molecular mechanisms underlying LA's anti-GC effects in vitro and in vivo.
- To identify potential molecular targets and signaling pathways affected by LA in GC cells.
Main Methods:
- Cell proliferation was assessed using CCK8 assays in multiple GC cell lines.
- Molecular targets were predicted via protein-protein interaction (PPI) analysis, with VEGFR-2 identified as a key target.
- Molecular docking, molecular dynamics (MD), and microscale thermophoresis (MST) were used to confirm LA-VEGFR-2 binding and affinity.
- Cell cycle, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) were analyzed using various assays (Hoechst, FCM, MMP, Transwell, WB).
- Signaling pathway involvement (PI3K/AKT, MEK/ERK) was investigated via Western blot (WB).
Main Results:
- Licoflavone A (LA) significantly inhibited the proliferation of human GC cell lines (SGC-7901, MKN-45, MGC-803).
- VEGFR-2 was confirmed as a direct molecular target of LA.
- LA demonstrated potent anti-GC effects by blocking cell cycle progression, inducing apoptosis, and suppressing migration, invasion, and EMT.
- LA's cytotoxic effects were linked to the inhibition of PI3K/AKT and MEK/ERK signaling pathways in VEGF-stimulated GC cells.
Conclusions:
- Licoflavone A (LA) possesses significant antitumor activity against gastric cancer (GC) both in vitro and in vivo.
- LA exerts its anti-GC effects by targeting VEGFR-2, leading to the modulation of cell proliferation, apoptosis, migration, invasion, and EMT.
- The findings highlight LA as a promising therapeutic candidate for GC, acting through the inhibition of critical signaling pathways like PI3K/AKT and MEK/ERK.
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