Modified Ginseng Extract Induces Apoptosis in HepG2 Cancer Cells by Blocking the CXCL8-Mediated Akt/Nuclear Factor-kappa B Signaling Pathway

Abstract

The cytokine C-X-C motif chemokine ligand 8 (CXCL8) is produced in the tumor microenvironment and has an important role in cancer pathogenesis. CXCL8 activates the nuclear factor (NF)-kappa B signaling. However, the role of NF-kappa B inactivation in apoptosis induced by negative regulation of CXCL8 remains unclear. Here, we assessed the effects of MRGX on the transcriptional activity of NF-kappa B and the expression of tumor necrosis factor (TNF)-alpha-stimulated target genes in liver cancer cells. Furthermore, we found that modified regular ginseng extract (MRGX)-mediated inhibition of NF-kappa B signaling induced apoptosis. Importantly, MRGX exerted strong activity, inhibiting TNF-alpha-induced expression of Akt and NF-kappa B in a concentration-dependent manner. Furthermore, MRGX inhibited the TNF-alpha-induced expression of genes encoding CXCL8, CXCL1, inducible nitric oxide synthase and intercellular adhesion molecule 1. MRGX also dowregulated Akt activation, and there was a significant decrease in Akt activation in HepG2 cells treated with CXCL8 siRNA. Conversely, CXCL8 overexpression increased Akt activation in MRGX-treated HepG2 cells. When Akt was silenced, MRGX treatment of HepG2 cells overexpressing CXCL8 decreased nuclear translocation of NF-kappa B, whereas Akt overexpression increased nuclear translocation of NF-kappa B in MRGX-treated HepG2 cells. Moreover, MRGX negatively regulated the TNF-alpha-mediated I kappa B/NF-kappa B pathway to promote Bax activation, resulting in caspase-3 activation and apoptosis. Taken together, these results indicated that MRGX inhibited CXCL8-mediated Akt/NF-kappa B signaling, which upregulated Bax activation and consequently induced apoptosis in HepG2 cells.