A New Molecule Drug WJ460 Inhibits The Migration And Proliferation Of Melanoma Cells And Its Mechanism

Melanoma is a highly lethal skin tumor caused by hyperproliferation of melanocyte cells.Since its high metastasis and proliferation capacity,melanoma cure rate is very low.In all skin cancer deaths,melanoma deaths accounted for 80%of the total number of deaths of all skin cancers.In recent years,due to environmental degradation and other factors,melanoma incidence and mortality continues to increase in the world.The high metastatic melanoma is the biggest obstacle to the treatment of melanoma,so it is important to find a drug that can inhibit melanoma metastasis and proliferation.The study of other research groups in our laboratory found that structural compounds with 2,3-diarylthiazolinone would have a better resistance effect on the migration and invasion of tumor cells.Based on this structure,the research group synthesized and modified a series of small molecule compounds.We use B16F10 melanoma cells in vitro scratch experiment on the obtained drug screening,to determine the best and most stable on melanoma anti migration effect of small molecule compounds WJ460.In vitro cell experiments,we investigated that WJ460 could indeed inhibit the migration of melanoma cells in a concentration-dependent manner by wound healing and transwell invasion experients,and that WJ460 could change the cell morphology of melanoma cells by fluorescence staining.In vivo animal experiments,we established a tumor lung metastasis model by tail vein injection of melanoma cells,intraperitoneal injection of WJ460,and the results show that WJ460 can effectively inhibit melanoma lung metastasis.Furthermore,we explore the molecular mechanism of drug action,the experimental results show that WJ460 can effectively inhibit the expression of EMT related molecules in transcription and protein levels including N-cadherin,E-cadherin,MMP-9,Vimentin,Slug,Twist et al.In addition,we found that WJ460 can regulate multiple signal pathways in melanoma cells,thereby inhibiting the expression of EMT-related molecules.The results showed that WJ460 could inhibit the phosphorylation of ERK1/2,GSK-3P and the expression of ?-catenin,thus inhibiting the activity of MAPK and Wnt/?-catenin signaling pathway.We demonstrated that WJ460 did inhibit these two signaling pathways by EGF and Wnt3a activator experiments to play an anti-tumor effect.Interestingly,in the verification process we found that the interactions between these two signaling pathways.EGF stimulation not only promoted the phosphorylation of ERK1/2,but increased the expression of ?-catenin,while EGF and WJ460 co-treatment can reduce the expression of ?-catenin.Through the stimulation of Wnt3a can promote the expression of ?-catenin,can also activate the phosphorylation of ERK1/2,and then after treat with WJ460,can inhibit the expression of ?-catenin and P-ERKl/2.This suggests that WJ460 may inhibit the metastasis of tumors by inhibiting MAPK and Wnt signal pathway,further inhibiting tumor metastasis.In summary,our study demonstrates that WJ460 has a good effect on inhibitor melanoma metastasis and proliferation,and the drug mechanism of action is through the inhibition of melanoma cells within the MAPK and Wnt/p-catenin signaling pathways.These provide a certain clinical value for Melanoma treatment.