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Urokinase receptor (uPAR) is enhanced in many human cancer cells and is frequently an indicator of poor prognosis. Activation of $\alpha 5\beta$1-integrin requires caveolin-1 and is regulated by uPAR. However, the underlying molecular mechanism responsible for the interaction between uPAR and $\alpha 5\beta$1-integrin remains obscure. We found that modified regular Panax ginseng extract (MRGX) had a negative modulating effect on the uPAR/$\alpha 5\beta$1-integrin interaction, disrupted the uPAR/integrin interaction by modulating caveoline-1, and caused early apoptosis in cancer cells. Additionally, we found that siRNA-mediated caveoline-1 downregulation inhibited uPAR-mediated $\alpha 5\beta$1-integrin signaling, whereas caveoline-1 up-regulation stimulated the signaling, which suppressed p53 expression, thereby indicating negative crosstalk exists between the integrin $\alpha 5\beta$1 and the p53 pathways. Thus, these findings identify a novel mechanism whereby the inhibition of $\alpha 5\beta$1 integrin and the activation of p53 modulate the expression of the anti-apoptotic proteins that are crucially involved in inducing apoptosis in A549 lung cancer cells. Furthermore, MRGX causes changes in the expressions of members of the Bcl-2 family (Bax and Bcl-2) in a pro-apoptotic manner. In addition, MGRX-mediated inhibition of $\alpha 5\beta$1 integrin attenuates ERK phosphorylation (p-ERK), which up-regulates caspase-8 and Bax. Therefore, ERK may affect mitochondria through a negative regulation of caspase-8 and Bax. Taken together, these findings reveal that MRGX is involved in uPAR-$\alpha 5\beta$1-integrin signaling by modulating caveolin-1 signaling to induce early apoptosis in A549 lung-cancer cells and strongly indicate that MRGX might be useful as a herbal medicine and may lead to the development of new herbal medicine that would suppress the growth of lung-cancer cells.

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.