Licochalcone A Suppresses Migration and Invasion of Human Hepatocellular Carcinoma Cells through Downregulation of MKK4/JNK via NF-κB Mediated Urokinase Plasminogen Activator Expression

Abstract

Hepatocellular cell carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and in Taiwan. Chemoprevention of cancer with dietary bioactive compounds could potentially reverse, suppress, or prevent cancer progression. Licochalcone A (LicA) is a characteristic chalcone of licorice, which is the root of Glycyrrhiza inflate. It had been reported that LicA has anti-inflammatory, anti-microbial, and anti-tumor properties. However, the effects of LicA on the migration and invasion of human HCC cells have not yet been reported. In the present study, it was found that LicA inhibits the migratory and invasion ability of SK-Hep-1 and HA22T/VGH cells in a dose-dependent manner, as assessed by the cell migration and Matrigel cell invasion assay. Using casein zymography, Western blotting, reverse transcriptase polymerase chain reaction, and an immunofluorescence assay, it was found that LicA induces a dose-dependent inhibition of uPA activity and expression, as well as reduces mRNA levels in SK-Hep-1 and HA22T/VGH cells. LicA was also found to inhibit the expression of phosphor-JNK and phosphor-MKK4 in SK-Hep-1 cells. Furthermore, LicA significantly decreased uPA levels in SP600125-treated or si-MKK4-transfected cells alongside a marked reduction in cell migration and invasion, which supports the notion that an inhibition of MKK4/JNK results in anti-metastatic effects. Moreover, LicA inhibited the expression of nuclear NF-κB, as well as the binding ability of NF-κB to the uPA promoter. These findings further our understanding of the role of LicA in suppressing tumor metastasis and its underlying molecular mechanisms, as well as suggest that LicA may be a promising anti-metastatic agent.

Licochalcone A, a natural chalconoid isolated from Glycyrrhiza inflata root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma

“…Recent studies have reported that LCA and LCE, retrochalcones derived from root of Glycyrrhiza inflata, reduces inflammation, migration, angiogenesis, tumorigenesis, is antidiabetic, inducing cell cycle arrest and apoptosis in various cancer cell lines both in vitro and in vivo (10,16,27). LCA has been reported to induce bladder cancer apoptosis via modulation of mitochondria dysfunction and endoplasmic reticulum stress (12).…”

“…Licorice, the root and rhizome of several Glycyrrhiza species (Leguminosae), is an important natural sweetening agent and Licochalcone A, a natural chalconoid isolated from Glycyrrhiza inflata root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma is widely used as a herbal medicine (3). Licochalcone A (LCA) is a novel flavonoid isolated from licorice root and is known to possess several bioactivities such as antioxidant, antibacterial, antiparasitic, anti-angiogenesis and antitumor effects (10)(11)(12). It reduces significantly TNF-α-induced NF-κB activation, consequently resulting in decreased inflammatory cytokines production (13,14).…”

Chemopreventive Effects of Licorice and Its Components

“…Decreased expression of phosphorylated p65 (a component of NF-κB) and N-cadherin (mesenchymal marker) and increased E-cadherin (epithelial marker) were also observed in LicAtreated SCC-25 cells [108]. LicA also attenuated the migratory and invasion ability of SK-Hep-1 and HA22T/VGH hepatic cancer cells [109]. This effect corresponded with an inhibition of the activity and expression of the serine protease, urokinase plasminogen activator (uPA), and decreased phosphorylation of JNKs and MKK4 in SK-Hep-1 cells [109].…”

“…LicA also attenuated the migratory and invasion ability of SK-Hep-1 and HA22T/VGH hepatic cancer cells [109]. This effect corresponded with an inhibition of the activity and expression of the serine protease, urokinase plasminogen activator (uPA), and decreased phosphorylation of JNKs and MKK4 in SK-Hep-1 cells [109]. Additionally, LicA suppressed the expression of NF-κB and its binding to the uPA promoter [109].…”

“…This effect corresponded with an inhibition of the activity and expression of the serine protease, urokinase plasminogen activator (uPA), and decreased phosphorylation of JNKs and MKK4 in SK-Hep-1 cells [109]. Additionally, LicA suppressed the expression of NF-κB and its binding to the uPA promoter [109]. Others reported that LicA effectively inhibited migration and invasion of A549 and H460 lung cancer cells [110].…”