Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis

Abstract

Angiogenesis and vasculogenic mimicry (VM) are considered to be the main processes to ensure tumor blood supply during the proliferation and metastasis of choroidal melanoma (CM). The traditional antimalarial drug artesunate (ART) has some potential anti-CM effects; however, the underlying mechanisms remain unclarified. Recent studies have shown that the Wnt5a/calmodulin-dependent kinase II (CaMKII) signaling pathway has a close correlation with angiogenesis and VM formation. This study demonstrated that ART eliminated VM formation by inhibiting the aforementioned signaling pathway in CM cells. The microvessel sprouting of the mouse aortic rings and the microvessel density of chicken chorioallantoic membrane (CAM) decreased significantly after ART treatment. VM formation assay and periodic acid schiff (PAS) staining revealed that ART inhibited VM formation in CM. Moreover, ART downregulated the expression levels of the angiogenesis-related proteins vascular endothelial growth factor receptor (VEGFR) 2, platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor (VEGF) A, and VM-related proteins ephrin type-A receptor (EphA) 2 and vascular endothelial (VE)-cadherin. The expression of hypoxia-inducible factor (HIF)-1α, Wnt5a, and phosphorylated CaMKII was also downregulated after ART treatment. In addition, we further demonstrated that ART inhibited the proliferation, migration, and invasion of OCM-1 and C918 cells. Collectively, our results suggested that ART inhibited angiogenesis and VM formation of choroidal melanoma likely by regulating the Wnt5a/CaMKII signaling pathway. These findings further supported the feasibility of ART for cancer therapy.

Novel artemisinin derivative P31 inhibits VEGF-induced corneal neovascularization through AKT and ERK1/2 pathways

“…In animal models, Cheng et al [ 42 ] demonstrated that artesunate could inhibit CoNV by inducing ROS-dependent apoptosis. Geng et al [ 43 ], suggest that Artesunate inhibits choroidal melanoma angiogenesis via the Wnt/CaMKII signaling axis.…”

Artesunate attenuates the tumorigenesis of choroidal melanoma via inhibiting EFNA3 through Stat3/Akt signaling pathway

“…ARPE-19 and Ocm-1 were bought from Beijing BeNa Culture Collection, C918 from Wuhan Procell Life Science & Technology Co., Ltd, Omm2.3 and Mel270 from Guangzhou Cellcook Biotech Co., Ltd. ART were purchased from Sigma. In previous study (Geng et al 2021 ), we examined the toxic effects of ART and the IC50 concentration in CM cells. The significance of EFNA3 in CM was analyzed using University of Alabama at Birmingham Cancer data analysis portal (UALCAN; https://ualcan.path.uab.edu/index.html ) and tumor immune estimation resources (TIMER v2.0; https://cistrome.shinyapps.io/timer/ ).…”

“…ART shows promise as an anticancer drug by inhibiting many classical pathways. Recent studies have also indicated that ART can suppress the progression of CM (Geng et al 2021 ; Farhan et al 2021 ). However, the exact mechanisms remain unclear and more research is needed.…”

Physicochemical aspects of the tumour microenvironment as drivers of vasculogenic mimicry

“…Also, the Wnt/β-catenin signalling pathway is involved in VM formation. It has been reported that Wnt/β-catenin signalling disruption decreases VM in colon cancer, triple-negative breast cancer, melanoma and osteosarcoma [166][167][168][169][170].…”