A novel synthetic oleanane triterpenoid suppresses adhesion, migration, and invasion of highly metastatic melanoma cells by modulating gelatinase signaling axis

Abstract

A methyl derivative natural triterpenoid amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) has been found to possess antiproliferative, proapoptotic, and antiinflammatory effects against established tumor cells. Large-scale synthesis of pure AMR-Me has eliminated the need of the natural phytochemical for further development of AMR-Me as an anticancer drug. Metastatic melanoma is a fatal form of cutaneous malignancy with poor prognosis and limited therapeutic options. It was hypothesized that antitumor pharmacological effect of AMR-Me could be linked to AMR-Me-mediated suppression of the metastatic potential of B16F10 murine melanoma. AMR-Me was assessed for its antimetastatic efficacy by cell adhesion, migration, and invasion assays in B16F10 cells. The signaling crosstalk was explored by gelatin zymography, Western blot, ELISA, and immunocytochemistry. The results elicited that AMR-Me was successful in restricting the adhesion, migration, and invasion of highly metastatic cells. The antimetastatic potential of this compound may be attributed to the reduced expression of membrane type 1 metalloproteinase (MT1-MMP) and matrix metalloproteinases (MMP-2 and MMP-9). AMR-Me was found to downregulate vascular endothelial growth factor (VEGF)/phosphorylated forms of focal adhesion kinase (pFAK397 )/Jun N-terminus kinase (pJNK)/extracellular signal-regulated kinase (pERK). This, in turn, inhibited transcription factor nuclear factor-κB (NF-κB) and transactivation of MMPs. Moreover, the activation of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) might have influenced the downmodulation of MT1-MMP, MMP-2, and MMP-9. AMR-Me suppresses the activity of MT1-MMP, MMP-2, and MMP-9 by downregulation of VEGF/pFAK397 /pJNK/pERK/NF-κB and activation of TIMP-1 and TIMP-2 in metastatic melanoma cell line, B16F10. AMR-Me has the potential as an effective anticancer drug for metastatic melanoma which is a dismal disease.