18β-glycyrrhetinic acid inhibited mitochondrial energy metabolism and gastric carcinogenesis through methylation-regulated TLR2 signaling pathway

Abstract

The natural phenolic substance, 18β-glycyrrhetinic acid (GRA), has shown enormous potential in the chemoprevention of cancers with rich resources and biological safety, but the GRA-regulated genetic and epigenetic profiles are unclear. Deregulated mitochondrial cellular energetics supporting higher adenosine triphosphate provisions relative to the uncontrolled proliferation of cancer cells is a cancer hallmark. The Toll-like receptor 2 (TLR2) signaling pathway has emerged as a key molecular component in gastric cancer (GC) cell proliferation and epithelial homeostasis. However, whether TLR2 influenced GC cell energy metabolism and whether the inhibition effects of GRA on GC relied on TLR2 signaling were not illustrated. In the present study, TLR2 mRNA and protein expression levels were elevated in gastric tumors in the K19-Wnt1/C2mE (Gan) mice model, GC cell lines and human GCs, and the overexpression of TLR2 was correlated with the high histological grade and was a poor prognostic factor in GC patients. Further gain and loss of function showed that TLR2 activation induced GC cell proliferation and promoted reactive oxygen species (ROS) generation, Ca2+ accumulation, oxidative phosphorylation and the electron transport chain, while blocking TLR2 inhibited mitochondrial function and energy metabolism. Furthermore, GRA pretreatment inhibited TLR2-activated GC cell proliferation, energy metabolism and carcinogenesis. In addition, expression of TLR2 was found to be downregulated by GRA through methylation regulation. Collectively, the results demonstrated that GRA inhibited gastric tumorigenesis through TLR2-accelerated energy metabolism, suggesting GRA as a promising therapeutic agency targeting TLR2 signaling in GC.

Analysis of Collagen type X alpha 1 (COL10A1) expression and prognostic significance in gastric cancer based on bioinformatics

“…Semaphorins and their receptors are significant axon guidance factors that participate in tumor cell migration [ 39 ]. The Toll-like receptor signaling pathway is critical for gastric cancer cell migration and proliferation [ 40 , 41 ]. The Notch signaling pathway is a crucial pathway in the occurrence and development of tumor [ 42 ].…”

Grafting of 18β-Glycyrrhetinic Acid and Sialic Acid onto Chitosan to Produce a New Amphipathic Chitosan Derivative: Synthesis, Characterization, and Cytotoxicity

“…18β-Glycyrrhetinic acid (GA) is released from glycyrrhizin through hydrolysis. It is extracted from the roots of licorice, and exhibits various anti-inflammatory [1][2][3][4][5], antioxidation [6][7][8][9], and antimicrobial activities [10]. GA is used widely in the pharmaceutical industry [11].…”

Identification and Validation of a Pyroptosis-Related Prognostic Model for Gastric Cancer

“…Moreover, DHX9 plays an important role in promoting the metastasis of colorectal cancer (Hou et al, 2021). TLR2 belongs to the Toll-like receptor family and is a key regulator of innate and acquired immune responses (Cao et al, 2019). We found that dendritic cells, macrophages, and neutrophils infiltration into CG tumors were positively correlated with the risk score.…”