Abstract
Bornyl cis-4-hydroxycinnamate, a bioactive compound isolated from Piper betle stems, has the potential for use as an anti-cancer agent. This study investigated the effects of bornyl cis-4-hydroxycinnamate on cell migration and invasion in melanoma cells. Cell migration and invasion were compared in A2058 and A375 melanoma cell lines treated with/without bornyl cis-4-hydroxycinnamate (1–6 µM). To examine whether bornyl cis-4-hydroxycinnamate has a potential anti-metastatic effect on melanoma cells, cell migration and invasion assays were performed using a Boyden chamber assay and a transwell chamber in A2058 and A375 cells. Gelatin zymography was employed to determine the enzyme activities of MMP-2 and MMP-9. Cell lysates were collected for Western blotting analysis of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors of metalloproteinase-1/2 (TIMP-1/2), as well as key molecules in the mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK)/ phosphatidylinositide-3 kinases (PI3K)/Akt/ mammalian target of rapamycin (mTOR), growth factor receptor-bound protein 2 (GRB2) signaling pathways. Our results demonstrated that bornyl cis-4-hydroxycinnamate is a potentially useful agent that inhibits melanoma cell migration and invasion, and altered melanoma cell metastasis by reducing MMP-2 and MMP-9 expression through inhibition of the FAK/PI3K/Akt/mTOR, MAPK, and GRB2 signaling pathways. Moreover, bornyl cis-4-hydroxycinnamate inhibited the process of the epithelial-to-mesenchymal transition in A2058 and A375 melanoma cells. These findings suggested that bornyl cis-4-hydroxycinnamate has potential as a chemotherapeutic agent, and warrants further investigation for its use in the management of human melanoma.
Highlights
Melanoma, a malignancy of melanocytes found predominantly in the skin, is the most dangerous form of cutaneous cancer, and its incidence is increasing throughout the world [1]
We evaluated the viability of another melanoma cell lines (B16–F10 cells) within various concentrations of bornyl cis-4-hydroxycinnamate by methylthiazole tetrazolium (MTT) assay
The results displayed that the viability of B16–F10 cells were similar to A2058 cells and A375 cells (Supplementary Figure S1).We chose a concentration (1, 3, and 6 μM) of bornyl cis-4-hydroxycinnamate for all subsequent experiments
Summary
A malignancy of melanocytes found predominantly in the skin, is the most dangerous form of cutaneous cancer, and its incidence is increasing throughout the world [1]. Surgery is the main treatment for early-stage melanoma [2,3], but it is rarely curative for the advanced stages. The therapy for most patients with advanced stages melanoma is chemotherapy and cytokine therapy; it presents poor responses. Dacarbazine, an anti-neoplastic agent used against malignant melanoma, has a response rate of 15–25% [4,5]. High-doses of interleukin (IL)-2, a form of cytokine therapy, has a response rate of only around 12.5% [6,7]. Metastatic melanoma has a very poor prognosis, with a low survival rate [8,9,10]. Development of new drugs to treat patients with malignant melanoma is an important issue
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