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Luteolin Suppresses Three Angiogenesis Modes and Cell Interaction in Uveal Melanoma in Vitro
Yu-Fen Chen1,2, Sha Wu1,2, Xuemei Li1,2,3
1Nanchang University, Nanchang, China.
Purpose:
Uveal melanoma is a high-vascularized tumor that lacks effective systemic therapies. Most anti-angiogenesis drug therapies only target endothelial cell-dependent angiogenesis but not vasculogenic mimicry (VM), which supplies blood to tumors independent of endothelial cells. Thus, we aimed to explore the inhibitory effects of luteolin on proliferation, migration, invasiveness, angiogenesis, and VM activity of uveal melanoma. We further explored the signaling pathway underlying the mechanism of action of luteolin.
Methods:
Monocultures of uveal melanoma C918 cells, human umbilical vein endothelial cells (HUVECs), and co-cultures of these two cell lines were established. Angiogenesis of HUVECs, VM formation of C918 cells, and the mosaic vessels formed by both cell types were observed under an inverted microscope. Cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU), wound scratch, Transwell cell migration, and invasion assays were performed. VEGF levels were detected by ELISA. Western blotting was used to detect the expression of PI3K, p-PI3K P85, Akt, and p-Akt Ser473 proteins.
Results:
Luteolin inhibited all three modes of angiogenesis observed in uveal melanoma in vitro. Luteolin effectively inhibited the proliferation, migration, and invasion of C918 cells and proliferation and migration of HUVECs. Furthermore, luteolin could inhibit the interaction between the endothelial cells and C918 cells. VEGF secretion in C918 cells and HUVECs treated with luteolin was inhibited. Luteolin decreased the levels of phosphorylated Akt kinase.
Conclusion:
We demonstrated the anti-angiogenic effects of luteolin, including against the VM type, in addition to suppressing tumor cell proliferation and migration in vitro. Furthermore, luteolin likely exerts its inhibitory effects via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Luteolin might be an effective therapeutic candidate for treating highly vascularized uveal melanoma tumors.
Insights
Luteolin effectively inhibits uveal melanoma cell growth, migration, and invasion. This natural compound also targets angiogenesis and vasculogenic mimicry, offering a potential new therapy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Uveal melanoma is a highly vascularized eye cancer lacking effective systemic treatments.
- Current anti-angiogenesis therapies often fail to address vasculogenic mimicry (VM), a key blood supply pathway in tumors.
Purpose of the Study:
- To investigate the inhibitory effects of luteolin on uveal melanoma cell proliferation, migration, invasiveness, angiogenesis, and VM.
- To explore the underlying signaling pathway of luteolin's mechanism of action.
Main Methods:
- Utilized monocultures and co-cultures of uveal melanoma (C918) and human umbilical vein endothelial cells (HUVECs).
- Assessed angiogenesis, VM, cell proliferation, migration, and invasion using microscopy and various assays (CCK-8, EdU, scratch, Transwell).
- Measured VEGF levels via ELISA and protein expression (PI3K/Akt pathway) via Western blotting.
Main Results:
- Luteolin inhibited all observed angiogenesis modes, including VM, in uveal melanoma cells.
- Luteolin suppressed proliferation, migration, and invasion of C918 cells and HUVECs.
- Luteolin reduced VEGF secretion and inhibited the PI3K/Akt signaling pathway.
Conclusions:
- Luteolin demonstrates significant anti-angiogenic and anti-VM effects, alongside inhibiting tumor cell proliferation and migration in vitro.
- Luteolin's therapeutic potential in uveal melanoma may be mediated through the PI3K/Akt signaling pathway.
- Luteolin presents a promising candidate for treating highly vascularized uveal melanoma.
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