Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer death worldwide. Astragalus polysaccharide (APS), the primary active component extracted from a traditional Chinese medicinal herb Astragalus membranaceus, has been proved to exert a marked inhibitory effect on a number of types of human solid tumors. In the present study, we aimed to examine the effects of APS on the survival of the HCC cell line H22 and to elucidate the underlying regulatory mechanisms responsible for these effects. Our results revealed that the mRNA and protein expression of Notch1 was significantly upregulated in the HCC tissues compared with that in the normal tissues. APS decreased cell viability and induced the apoptosis of HCC cells in a concentration-dependent manner, which were evaluated using a cell counting kit-8 (CCK-8) assay and flow cytometric analysis, respectively. Furthermore, APS regulated the expression of apoptosis-related genes (Bcl-2 and BAX) and proteases (caspase-3 and -8). Mechanically, Notch1 expression was found to be suppressed in HCC cells, and further analysis indicated that Notch1 knockdown by siRNA significantly reduced cell viability, suppressed the metastatic capacity and enhanced the apoptosis of HCC cells. Taken together, these findings suggest that Notch1 may be a potential therapeutic target for the treatment of HCC.
BackgroundAnaerobic glycolysis is an important physiological process of all cancer cells. Butein has been reported to demonstrate substantial antitumor activities in various cancers. However, the effect of butein on tumor glycolysis remains unclear. In this study, the effect of butein on tumor glycolysis and the underlying mechanism were investigated in hepatocellular carcinoma (HCC).Material/MethodsCell proliferation assay and anchorage-independent growth assay were carried out to evaluate the antitumor activities of butein in vitro. The effect of butein on tumor glycolysis was determined by examining the changes in glucose uptake and lactate production. Hexokinase-2 (HK-2) expression in HCC cells upon butein treatment was analyzed by Western blotting. The activity of butein on EGFR signaling pathway was studied and its potency in EGFR exogenous overexpression cells was investigated.ResultsAfter butein treatment, HCC cell proliferation was significantly inhibited (91.4% in Hep3B and 88.2% in Huh-7 at 80 μM, p<0.001). Moreover, the number of colonies formed in the agar was substantially decreased (93.8% in Hep3B and 72.3% in Huh-7 at 80 μM, p<0.001). With the suppression of HK-2 expression, glucose consumption in Hep3B and Huh-7 cells decreased by 48.4% and 56.3%, respectively (p<0.01), and the lactate production also was reduced accordingly (39.5% in Hep3B and 48.6% in Huh-7, p<0.01). Mechanism investigations demonstrated that butein dose-dependently blocked the activation of the EGFR signaling pathway in HCC cells. In EGFR exogenous overexpression cells, the glycolysis suppression exerted by butein was substantially attenuated.ConclusionsButein has a substantial inhibitory effect on tumor glycolysis in HCC cells, and the glycolysis suppression exerted by butein is closely related to its effect on the EGFR signaling pathway.
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