Salvigenin Suppresses Hepatocellular Carcinoma Glycolysis and Chemoresistance Through Inactivating the PI3K/AKT/GSK-3β Pathway

Abstract

Salvigenin is a Trimethoxylated Flavone enriched in Scutellariae Barbatae Herba and Scutellariae Radix and is demonstrated to have anti-tumor properties in colon cancer. Notwithstanding, the function and mechanism of Salvigenin in hepatocellular carcinoma (HCC) are less well studied. Different doses of Salvigenin were taken to treat HCC cells. Cell viability, colony formation ability, cell migration, invasion, apoptosis, glucose uptake, and lactate production levels were detected. As shown by the data, Salvigenin concentration dependently dampened HCC cell proliferation, migration, and invasion, weakened glycolysis by abating glucose uptake and lactate generation, and suppressed the profiles of glycolytic enzymes. Moreover, Salvigenin strengthened HCC cells’ sensitivity to 5-fluorouracil (5-FU) and attenuated HCC 5-FU-resistant cells’ resistance to 5-FU. Through network pharmacological analysis, we found Salvigenin potentially regulates PI3K/AKT pathway. As shown by the data, Salvigenin repressed the phosphorylated levels of PI3K, AKT, and GSK-3β. The PI3K activator 740Y-P induced PI3K/AKT/GSK-3β pathway activation and promotive effects in HCC cells. However, Salvigenin substantially weakened 740Y-P-mediated effects. In-vivo assay revealed that Salvigenin hampered the growth and promoted apoptosis of HCC cells in nude mice. Collectively, Salvigenin impedes the aerobic glycolysis and 5-FU chemoresistance of HCC cells by dampening the PI3K/AKT/GSK-3β pathway.

Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma

“…Moreover, lactic acid accumulation inhibits the immune process 21 , and leads to tumor immune escape via impairing tumor surveillance by T or NK cells 11 . Remodeling glycolysis is a common phenomenon in HCC, which is associated with HCC progression 22 , lenvatinib 23 and chemoresistance 24 . Lactic acid accumulates in HCC TME during aerobic glycolysis, and histone Kla is sensitive to lactate level.…”