Alpha-Mangostin Suppresses the Metastasis of Human Renal Carcinoma Cells by Targeting MEK/ERK Expression and MMP-9 Transcription Activity

Abstract

Background/Aims: α-mangostin has anti-carcinogenic effects against several cancers. We investigated the molecular mechanism of this compound on the metastasis of human renal carcinoma cells. Methods: Cell viability was measured using the MTT assay, and cell cycle distribution using flow cytometry. A Matrigel-based assay was used to measure in vitro cell migration and invasion. MAPK-related proteins and matrix metalloproteinase (MMP)-9 and MMP-2 expression were measured by western blotting, and MMP2/-9 activities were determined by gelatin zymography. RT-qPCR and a luciferase assay were used to examine the transcriptional activity of MMP-9. Results: α-mangostin inhibited the migration and invasion of RCC cells in a dose-dependent manner, but had no evident cytotoxic effects. Treatment of 786-O cells with α-mangostin inhibited activation of MEK and ERK. Treatment with a specific MEK inhibitor (U0126) enhanced the inhibitory effects of α-mangostin on cell migration and invasion, and the phosphorylation of ERK and MEK. Moreover, α-mangostin inhibited the expression of the MMP-9 mRNA levels as well as the activity of MMP-9 promoter, and these suppressive effects were further enhanced by U0126. Conclusions: Our results suggest that α-mangostin suppresses cell migration and invasion via MEK/ERK/MMP9 pathway, and might be a promising anti-metastatic agent against human renal cell carcinoma.

BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma

“…In our experimental setting, the mechanism underlying the BMP9mediated regulation of these functions seem to involve the RhoA-Cofilin axis which, together with MMP9 are subjected to a strong BMP9-dependent reduction of their levels. In this context, PI3K/AKT and MEK/ERK have been reported to regulate the metastatic potential of cancer cells through a positive control of MMP9 expression [52,53], Many authors already reported a potent prodifferentiating activity triggered by BMP2 [5,22], BMP4 [20] and BMP7 [19,23,24] on GSCs. In these studies, activation of BMP signaling was sufficient to dramatically inhibit the stem-like properties of primary GBM cultures both in vitro and in vivo, by inducing a multi-lineage neural differentiation.…”

<p>Nanoparticle Drug Delivery Systems for α-Mangostin</p>

“…[1][2][3][4][5] The anticancer activity indicates that α-mangostin might serve as a potent anticancer agent in lung, stomach, colon, cervical, pancreatic, prostate, mammary gland, chondrosarcoma, renal, skin, tongue mucoepidermoid and breast cancers. [6][7][8][9][10][11][12][13][14][15][16][17][18] However, αmangostin has low solubility in water (2.03 x 10 −4 mg/L at 25ºC), and many efforts have been made to improve it: structure modification, co-solvation, solid dispersion, emulsion, complexation and nanoparticle drug delivery systems. [19][20][21] Additionally, αmangostin and other cytotoxic drugs generally have limitations that influence their effectiveness, including a first fast metabolism reaction, an efflux reaction induced by transporter intercellular, fast drug release and a non-specific target site.…”

Matrine inhibits the invasive and migratory properties of human hepatocellular carcinoma by regulating epithelial‑mesenchymal transition

“…MMPs serve a central role in tumor EMT by the cleavage of components of the ECM and the endothelial cell basement membrane. MMP2 and MMP9, members of the MMP family, have been demonstrated in cancer tissues, and are associated with the processes of tumor aggression, and metastasis in human cancer ( 9 ). Furthermore, a previous study reported that MMP2 and MMP9 could break down cell surface associated molecules ( 10 ), and could cleave the E-cadherin ectodomain near the plasma membrane into soluble E-cadherin ( 11 ), which may be involved in MMPs-enhanced invasion and metastatic potential of cancer cells.…”