Abstract
NecroX-5 (NX-5) is a cell-permeable necrosis inhibitor with cytoprotective effects. Although it has been reported to inhibit lung and breast cancer metastasis by modulating migration, its therapeutic effect on melanoma metastasis is still unknown. In this study, we examined the anti-metastatic effect of NX-5 on melanoma cell lines and its related therapeutic mechanism. The anti-metastatic effect of NX-5 on melanoma cell lines was determined using a transwell migration assay. We performed a quantitative real-time polymerase chain reaction and western blot analysis to measure changes in the expression of mRNA and protein, respectively, for major mediators of Rho-family GTPases after NX-5 treatment in melanoma cells. In addition, after constructing the 3D melanoma model, the expression of Rho-family GTPases was measured by immunohistochemistry. NX-5 (10 μM and 20 μM) treatment significantly reduced melanoma cell migration (p < 0.01). Additionally, NX-5 (20 μM) treatment significantly decreased the mRNA and protein expression levels of Cdc42, Rac1, and RhoA in melanoma cells compared with the untreated group (p < 0.001 and p < 0.05, respectively). Immunohistochemistry for our 3D melanoma model showed that Cdc42, Rac1, and RhoA were constitutively expressed in the nuclei of melanoma cells of the untreated group, and NX-5 treatment decreased their expression. These results demonstrate that NX-5 can suppress melanoma metastasis by reducing the expression of Rho-family GTPases.
Highlights
Melanoma is a fatal disease that accounts for 90% of skin cancer-related deaths, and metastasis occurs with a poor prognosis [1,2]
NX-5 nomaconcentrations cell migration.(Figure 2). These results demonstrated that NX-5 can reduce melamelanoma cell migration
NX-5 treatment decreased A375P and A375SM cell migration. This result was elucidated by reducing the expression of Rho-family GTPases (Cdc42/Rac1/RhoA)
Summary
Melanoma is a fatal disease that accounts for 90% of skin cancer-related deaths, and metastasis occurs with a poor prognosis [1,2]. Most melanomas metastasize to distant organs such as the liver, bones, and brain; skin, subcutaneous tissue, and lymph nodes are the primary sites of metastasis [3]. Cancer metastasis is a process of cell migration, epithelial-mesenchymal transition (EMT), intravascular invasion, the potential circulation of tumor cells, and deposition to secondary organs. Rho-family GTPases have Cdc, Rac, and RhoA as the main subfamily and play important roles in various cell functions including angiogenesis and invasion, cytoskeletal structure formation, cell proliferation, apoptosis, and cancer metastasis [8,9,10]. Cdc contributes both amoeboid and mesenchymal movement and overall tumor cell invasion. When Rhofamily GTPases move to the cell membrane and are activated, they induce cancer cell transplantation and metastasis through downstream target molecules [15].
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