Methyl Gallate Suppresses the Migration, Invasion, and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma Cells via the AMPK/NF-κB Signaling Pathway in vitro and in vivo

Abstract

Methyl gallate (MG), a polyphenolic compound found in plants, is widely used in traditional Chinese medicine. MG is known to alleviate several cancer symptoms. However, most studies that have reported the antitumor effects of MG have done so at the cellular level, and the inhibitory effect and therapeutic mechanism of MG in hepatocellular carcinoma (HCC) have not been extensively explored in vivo. We aimed to understand the therapeutic mechanism of MG in HCC in vitro and in vivo. MTT and colony formation assays were used to determine the impact of MG on the proliferation of a human HCC cell line, BEL-7402; wound healing and transwell assays were used to quantify the migration and invasion of HCC cells. Western blotting was used to quantify the expression of the AMPK/NF-κB signaling pathway proteins. In vivo tumor growth was measured in a xenograft tumor nude mouse model treated with MG, and hematoxylin–eosin staining and immunohistochemistry (IHC) were used to visualize the histological changes in the tumor tissue. We found that MG showed anti-proliferative effects both in vitro and in vivo. MG downregulated the protein expression of AMPK, NF-κB, p-NF-κB, and vimentin and upregulated the expression of E-cadherin in a dose-dependent manner. Additionally, MG inhibited the migration and invasion of HCC cells by decreasing MMP9 and MMP2 expression and increasing TIMP-2 expression. These were consistent with the results of IHC in vivo. MG inhibited the proliferation, migration, and invasion of HCC cells. This effect potentially involves the regulation of the AMPK/NF-κB pathway, which in turn impacts epithelial-mesenchymal transition and MMP expression.

A Deadly Liaison between Oxidative Injury and p53 Drives Methyl-Gallate-Induced Autophagy and Apoptosis in HCT116 Colon Cancer Cells

“…Studies on the cytotoxic effects of MG demonstrated that this phytochemical elicits remarkable cell viability inhibition in many tumor systems [ 29 , 31 ]. However, since no data are available for colon cancer, we undertook a study aimed at evaluating the MG antitumor potential on the viability of two colon cancer cell lines (HCT116 and Caco-2).…”

“…Additionally, MG was also shown to exert a tumor inhibitory effect in in vitro and in vivo mouse models of hepatocellular carcinoma. Furthermore, it did not exert any cytotoxic effect in human normal hepatocytes, while it significantly suppressed the migration, invasion and epithelial–mesenchymal transition in tumor systems of HCC via the AMPK/NF-κB pathway [ 31 ].…”

Gliclazide Reduces Colitis-Associated Colorectal Cancer Formation by Deceasing Colonic Inflammation and Regulating AMPK-NF-κB Signaling Pathway

“…Gliclazide induces AMPK activation and inhibits vascular smooth muscle cell proliferation in a dose- and time-dependent manner [ 9 ]. AMPK-NF-κB signaling participates in the pathogenesis of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and hepatocellular carcinoma by regulating proliferation, migration, and invasion [ 10 , 11 ]. However, it is unknown whether gliclazide regulates AMPK-NF-κB signaling in CAC.…”

Microemulsion based on methyl 3,4,5-trihydroxybenzoate for the topical treatment of cutaneous leishmaniasis: an in vivo assay

“…Methyl gallate can exert pharmacological effects through multiple pathways and targets, such as PI3K-Akt, ERK1-2, Caspase, AMPK-NFkB, Wnt-β-catenin, TLR4-NF-kB, MAPK, p53, NLRP3, ROS, EMT (Liang et al 2023). It is thus possible that the reduction of the leishmaniotic lesion and the parasitic load in our study in the golden hamsters treated with the methyl gallate microemulsion on its own or in combination with Glucantime ® may be related to activation or deactivation of any of these pathways.…”