Wogonin inhibits the proliferation and invasion, and induces the apoptosis of HepG2 and Bel7402 HCC cells through NF-κB/Bcl-2, EGFR and EGFR downstream ERK/AKT signaling

Abstract

The anticancer effects of the natural flavonoid, wogonin, have been reported. However, its molecular mechanisms of action have not yet been fully explored. In the present study, we aimed to examine the molecular mechanisms of action of wogonin and its effects on the biological behavior of the HepG2 and Bel7402 hepatocellular carcinoma (HCC) cell lines. We also examined the effects of wogonin on nuclear factor-κB (NF-κB)/Bcl-2 and epidermal growth factor receptor (EGFR) signaling, as well as on downstream pathways of EGFR, namely extracellular signal-regulated kinase (ERK)/AKT signaling. We found that treatment with wogonin inhibited the proliferation and invasion, and induced the apoptosis of the HepG2 and Bel7402 cells. In addition, treatment with wogonin decreased cyclin D1, cyclin E, CDK4/6, Bcl-2 and matrix metalloproteinase 2 (MMP2) expression, and promoted the cleavage of caspase-3 and caspase-9 in a concentration-dependent manner. Further experiments revealed that wogonin inhibited NF-κB/Bcl-2 signaling by decreasing the IκB and p65 phosphorylation levels. Wogonin also inhibited the activation of the EGFR (Tyr845) signaling pathway, and that of downstream pathways of EGFR, namely ERK/AKT/MMP2 signaling. The depletion of EGFR by siRNA partly abolished the inhibitory effects of wogonin on cyclin D1, MMP2 expression. On the whole, our our findings demonstrate that wogonin effectively suppresses the proliferation, invasion and survival of HCC cells through the modulation of the NF-κB and EGFR signaling pathways.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Wogonin also enhances ROS production in human glioma U251 and U87, pancreatic cancer Panc-1 and Colo-357, and NSCLC A549 cells [711,721,729]. Moreover, it inhibits cell growth and induces apoptosis through NF-κB suppression in Epstein-Barr virus-positive lymphoma cells [730], and suppresses cell proliferation and invasion through NF-κB/Bcl-2 and EGFR pathways in human hepatocellular carcinoma HepG2 and Bel-7402 cells [717].…”

“…However, inhibition of autophagy promotes wogonin-induced apoptosis in human nasopharyngeal carcinoma NPC-TW076 and NPC-TW039 cells [722]. It also inhibits metastasis in human hepatocellular carcinoma Bel-7402 and HepG2 cells, and NSCLC A549 cells [717,723], and through MMP-9 suppression in human hepatocellular carcinoma MHCC97-L and PLC/PRF/5 cells [724]. In addition, wogonin also represses multiple myeloma-stimulated angiogenesis through c-Myc/von Hippel-Lindau tumor suppressor (VHL)/HIF-1α signaling pathway [725], LPSand H 2 O 2 -induced angiogenesis through PI3K/Akt/ NF-κB pathway [726,727].…”

“…Wogonin can induce apoptosis and inhibit cell proliferation in human neuroblastoma SK-N-BE2 and IMR-32, NSCLC A549, glioma U251 and U87, and hepatocellular carcinoma HepG2 and Bel-7402 cells [704,706,711,717]. It also induces cell cycle arrest in human colorectal cancer HCT-116, NSCLC A549, chronic myelogenous leukemia imatinib-resistant K562, and ovarian cancer A2780 cells [716,[718][719][720].…”

Wogonin Suppresses the Activity of Matrix Metalloproteinase-9 and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma

“…Wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid-like chemical compound found in Radix Scutellariae, is a well-known herbal agent which has shown remarkable anticarcinogenic and chemopreventive capacity in various studies [ 10 , 11 , 12 ]. In recent years, numerous evidences have demonstrated that wogonin effectively inhibited the invasion and migration of human gallbladder carcinoma [ 13 ] and breast cancer [ 14 ].…”

Sustained Cytotoxicity of Wogonin on Breast Cancer Cells by Encapsulation in Solid Lipid Nanoparticles

“…Wogonin (5,7-dihydroxy-8-methoxy flavone) is one of the active compounds of the flavonoids isolated from the radix of Scutellaria baicalensis and possesses anticancer properties in a wide range of human cancer cell lines by inducing apoptosis in vitro [ 1 , 2 , 3 , 4 ]. A few studies have reported that wogonin (10–30 µmol/L) allows for enhanced cellular uptake of anticancer drugs in a few cancer cell lines [ 5 , 6 ].…”