Butein Inhibited In Vitro Hexokinase-2-Mediated Tumor Glycolysis in Hepatocellular Carcinoma by Blocking Epidermal Growth Factor Receptor (EGFR)

Abstract

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.

Effect of butein and glucose on oxidative stress and p38 activation marker in non-small cell lung cancer cell

“…The half maximal inhibitory concentration of butein in NSCLCCs was found to be 61.8 mM at 24 h. We have chosen the concentration butein based on the present and previously reported studies. 16,40 To our surprise, we observed that, irrespective of different concentrations of glucose, butein showed similar anticancer activity. In liver cancer cells, butein has shown its anticancer activity through the inhibition of HK II activity, 40 which is overexpressed in different solid tumors as well.…”

“…16,40 To our surprise, we observed that, irrespective of different concentrations of glucose, butein showed similar anticancer activity. In liver cancer cells, butein has shown its anticancer activity through the inhibition of HK II activity, 40 which is overexpressed in different solid tumors as well. Further, this enzyme is also overexpressed in anaerobic glycolysis.…”

An Investigation on the Therapeutic Potential of Butein, A Tretrahydroxychalcone Against Human Oral Squamous Cell Carcinoma

“…For instance, Yang et al, (2018) reported that butein reduced the viability of cervical cancer cells through a proapoptotic effect by blocking inhibitor of apoptosis (IAP) proteins and activating extrinsic as well as intrinsic proapoptotic cascades. Further, it inhibited the proliferation and survival of HCC ells effectively (Liao et al, 2018;Zhou et al, 2018). In addition, butein was also reported to exert its antiproliferative and pro-apoptotic effect through inhibition of NF-κB, AP-1 and Akt signaling in HTLV-1infected T cells in both in vitro and in vivo settings clearly indicating its therapeutic potential against adult T-cell leukemia/lymphoma (Ishikawa et al, 2017).…”

“…Similarly, the preceding reports have also suggested the same activities against different cancer cells such as breast, blood, liver, cervical etc. (Yang et al, 2012;Liao et al, 2018;Tang et al, 2016;Yang et al, 2018). For instance, Yang et al, (2018) reported that butein reduced the viability of cervical cancer cells through a proapoptotic effect by blocking inhibitor of apoptosis (IAP) proteins and activating extrinsic as well as intrinsic proapoptotic cascades.…”

Butein induces cellular senescence through reactive oxygen species‐mediated p53 activation in osteosarcoma U‐2 OS cells

“…Butein suppresses the cell viability of non‐small cell lung cancer through ER stress‐dependent ROS generation and apoptosis pathway 31 . Butein inhibits cell proliferation and glycolysis in hepatocellular carcinoma through suppressing epidermal growth factor receptor (EGFR) signaling pathway 36 . Butein suppresses migration and invasion of cancer cells through inhibiting the activity of matrix metalloproteinases 2 (MMP‐2) and metalloproteinases 9 (MMP‐9), and the expression of vascular endothelial growth factor (VEGF) 37,38 .…”