The Effect of Alpha Mangostin on Epithelial-Mesenchymal Transition on Human Hepatocellular Carcinoma HepG2 Cells Surviving Sorafenib via TGF-β/Smad Pathways

Abstract

Purpose : This study was intended to find out the impact of alpha mangostin administration on the epithelial-mesenchymal transition (EMT) markers and TGF-β/Smad pathways in hepatocellular carcinoma Hep-G2 cells surviving sorafenib. Methods: Hepatocellular carcinoma HepG2 cells were treated with sorafenib 10 μM. Cells surviving sorafenib treatment (HepG2surv) were then treated vehicle, sorafenib, alpha mangostin, or combination of sorafenib and alpha mangostin. Afterward, cells were observed for their morphology with an inverted microscope and counted for cell viability. The concentrations of transforming growth factor (TGF)-β1 in a culture medium were examined using ELISA. The mRNA expressions of TGF-β1, TGF-β1-receptor, Smad3, Smad7, E-cadherin, and vimentin were evaluated using quantitative reverse transcriptase–polymerase chain reaction. The protein level of E-cadherin was also determined using western blot analysis. Results: Treatment of alpha mangostin and sorafenib caused a significant decrease in the viability of sorafenib-surviving HepG2 cells versus control (both groups with P<0.05). Our study found that alpha mangostin treatment increased the expressions of vimentin (P<0.001 versus control). In contrast, alpha mangostin treatment tends to decrease the expressions of Smad7 and E-cadherin (both with P>0.05). In line with our findings, the expressions of TGF-β1 and Smad3 are significantly upregulated after alpha mangostin administration (both with P<0.05) versus control. Conclusion: Alpha mangostin reduced cell viability of sorafenib-surviving HepG2 cells; however, it also enhanced epithelial–mesenchymal transition markers by activating TGF-β/Smad pathways.

Alpha Mangostin Derived from <i>Garcinia magostana</i> Linn Ameliorates Cardiomyocyte Hypertrophy and Fibroblast Phenotypes <i>in Vitro</i>

“…α-Man has exhibited anti-cancer effects in pancreatic cancer cells through repression of PI3K/Akt signaling pathways, 44) whereas in INS-1 cells, it significantly increases insulin secretion via activation of the PI3K/Akt pathways. 45) Similarly, α-man exerts opposite effects on TGF-β pathways in hepatic stellate cells and HepG2 cells. 29,46) These findings suggest that α-man function differently depending on the cell type.…”

“…45) Similarly, α-man exerts opposite effects on TGF-β pathways in hepatic stellate cells and HepG2 cells. 29,46) These findings suggest that α-man function differently depending on the cell type. Further studies are required to elucidate the mechanisms by which α-man regulates cardiac hypertrophy and fibrosis.…”

Alpha-mangostin reduces cell viability in sorafenib-surviving cells by modulating multiple drug transporters in HepG2 hepatocellular carcinoma cells

“…Additionally, a recent study has demonstrated the chemosensitizing effect of AM, leading to its use as adjunctive treatment to the available anticancer chemotherapeutic agent. Adenina et al (2020)…”

“…To select SOR-surviving cells, HepG2 was incubated with SOR 10 mM for 24 hours. Cells that survived 24-hour SOR 10 mM incubation were then considered SOR-surviving cells described by Adenina et al (2020). Afterward, the medium was changed, and the cells were treated 24 hours with DMSO or SOR 10, AM 20 mM, or a combination of SOR 10 and AM 20 mM.…”

“…In a recent study, Adenina et al (2020) reported that the addition of AM to SOR in HCC cells' surviving SOR showed beneficial effect. However, the mechanism of how AM reduces cell viability in the previous system has not yet been elucidated.…”