Cui Zhen Yang, Jo Eunbi, Jang Hyun Jin, Hwang In-Hu, Lee Kyung-Bok, Yoo Hwa-Seung, Park Soo Jung, Jung Mi-Kyung, Lee Yeon Wol, Jang Ik-Soon
* Department of Sasang Constitutional Medicine, Wonkwang University, Iksan 54538, Republic of Korea.
† Department of Life Science and Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul 04763, Korea.
Am J Chin Med. 2018 Oct 4:1-18. doi: 10.1142/S0192415X18500842.
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)-B signaling. However, the role of NF-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-B and the expression of tumor necrosis factor (TNF)--stimulated target genes in liver cancer cells. Furthermore, we found that modified regular ginseng extract (MRGX)-mediated inhibition of NF-B signaling induced apoptosis. Importantly, MRGX exerted strong activity, inhibiting TNF--induced expression of Akt and NF-B in a concentration-dependent manner. Furthermore, MRGX inhibited the TNF--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-B, whereas Akt overexpression increased nuclear translocation of NF-B in MRGX-treated HepG2 cells. Moreover, MRGX negatively regulated the TNF--mediated IB/NF-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-B signaling, which upregulated Bax activation and consequently induced apoptosis in HepG2 cells.
细胞因子C-X-C基序趋化因子配体8（CXCL8）在肿瘤微环境中产生，在癌症发病机制中起重要作用。CXCL8激活核因子（NF）-κB信号传导。然而，NF-κB失活在CXCL8负调控诱导的细胞凋亡中的作用仍不清楚。在此，我们评估了改良常规人参提取物（MRGX）对肝癌细胞中NF-κB转录活性和肿瘤坏死因子（TNF）-α刺激的靶基因表达的影响。此外，我们发现MRGX介导的NF-κB信号传导抑制诱导了细胞凋亡。重要的是，MRGX具有强大的活性，以浓度依赖性方式抑制TNF-α诱导的Akt和NF-κB表达。此外，MRGX抑制TNF-α诱导的编码CXCL8、CXCL1、诱导型一氧化氮合酶和细胞间黏附分子1的基因表达。MRGX还下调Akt激活，在用CXCL8 siRNA处理的HepG2细胞中Akt激活显著降低。相反，CXCL8过表达增加了MRGX处理的HepG2细胞中的Akt激活。当Akt沉默时，MRGX处理过表达CXCL8的HepG2细胞会降低NF-κB的核转位，而Akt过表达则会增加MRGX处理的HepG2细胞中NF-κB的核转位。此外，MRGX负调控TNF-α介导的IκB/NF-κB途径以促进Bax激活，从而导致caspase-3激活和细胞凋亡。综上所述，这些结果表明MRGX抑制CXCL8介导的Akt/NF-κB信号传导，上调Bax激活，从而诱导HepG2细胞凋亡。
