Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

Abstract

Abstract.Tetrandrine has been shown to reduce cancer cell proliferation and to inhibit metastatic effects in multiple cancer models in vitro and in vivo. However, the effects of tetrandrine on the underlying mechanism of HT29 human colorectal adenocarcinoma cell metastasis remain to be fully elucidated. The aim of the present study was focused on tetrandrine-treated HT29 cells following epidermal growth factor (EGF) treatment, and Transwell, gelatin zymography, gene expression and immunoblotting assays were performed to investigate metastatic effects in vitro. Tetrandrine was observed to dose-dependently inhibit EGF-induced HT29 cell invasion and migration, however, no effect on cell viability occurred following exposure to tetradrine between 0.5 and 2 µM. Tetrandrine treatment inhibited the enzymatic activity of matrix metalloprotease (MMP)-2 and MMP-9 in a concentration-dependent manner. The present study also found a reduction in the mRNA expression levels of MMP-2 and MMP-9 in the tetrandrine-treated HT29 cells. Tetrandrine also suppressed the phosphorylation of EGF receptor (EGFR) and its downstream pathway, including phosphoinositide-dependent kinase 1, phosphatidylinositol 3-kinase and phosphorylated AKT, suppressing the gene expression of MMP-2 and MMP-9. Furthermore, tetrandrine triggered mitogen-activated protein kinase signaling through the suppressing the activation of phosphorylated extracellular signal-regulated protein kinase. These data suggested that targeting EGFR signaling and its downstream molecules contributed to the inhibition of EGF-induced HT29 cell metastasis caused by tetrandrine, eventually leading to a reduction in the mRNA and gelatinase activities of MMP-2 and MMP-9, respectively. IntroductionEpidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases (1), and EGFR activation by ligand binding stimulates multiple signals, including phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB pathways, ultimately resulting in cellular proliferation, survival, angiogenesis invasion and metastasis (2,3). Abnormal protein activity and/or expression levels of EGFR have been correlated with the etiology of several types of human cancer, including colorectal cancer (4,5), non-small cell lung cancer (6,7), breast cancer (8,9), head and neck squamous cell carcinoma (10,11), pancreatic cancer (12) and brain cancer (13). EGFR-targeted therapy has been validated in human colorectal cancer (14), and the chemotherapeutics include pharmacological agents, including cetuximab (Erbitux), which is an EGFR inhibitor (15). EGFR acts to bind an EGFR-selective ligand activated by epidermal growth factor (EGF), transforming growth factor-α, amphiregulin or neuregulin, finally leading to cell proliferation, invasion and the inhibition of apoptosis (15)(16)(17).Tetrandrine is a bisbenzylisoquinoline alkaloid, which is isolated from the dried root of Stephania tetrandra of the

Tetrandrine inhibits human brain glioblastoma multiforme GBM 8401 cancer cell migration and invasion in vitro

“…Human brain Glioblastoma multiforme cancer GBM 8401 cell line was purchased from the Food Industry Research and Development Institute (Hsinchu, Taiwan). Cells were cultured in RPMI‐1640 medium supplemented with 10% FBS, 100 units/mL penicillin and 100 μg/mL streptomycin at 37°C in a 75 cm 2 tissue culture flasks under humidified atmosphere with 5% CO 2 …”

“…Tetrandrine (TET), a bisbenzylisoquinoline alkaloid isolated from the root of Stephania tetrandra S. Moore , has been revealed to induce cell apoptosis in many human cancer cell lines and inhibits migration and invasion in human prostate cancer cells . Furthermore, TET suppresses cancer angiogenesis and metastasis in 4 T1 tumor bearing mice and targets on epidermal growth factor‐induced invasion and migration in HT29 human colorectal adenocarcinoma cells . TET inhibits Wnt/β‐catenin pathway and decreases metastatic tumor antigen 1 (MTA1) expression to modulate hepatocellular carcinoma cell metastasis .…”

Anticancer activity of tetrandrine by inducing pro-death apoptosis and autophagy in human gastric cancer cells

“…Tetrandrine was also found to induce cytotoxicity and apoptosis of human nasopharyngeal carcinoma cells via inducing ROS‐dependent mitochondrial and ER stress pathways and activating Akt/FOXO3 . Inhibition of tumour angiogenesis and metastasis by tetrandrine was gained through modulating ERK and EFGR pathways in human colorectal adenocarcinoma cells . It has been reported that tetrandrine extensive anticancer effects on gastric cancer cells, such as BGC‐823 cells; however, the potential molecular mechanism of tetrandrine on autophagy pathway in gastric cancer cells has not been clearly illuminated.…”

Tetrandrine suppresses adhesion, migration and invasion of human colon cancer SW620 cells via inhibition of nuclear factor-κB, matrix metalloproteinase-2 and matrix metalloproteinase-9 signaling pathways

“…It was also reported that TET regulates metastatic- and angiogenic-associated proteins, including vascular endothelial growth factor, hypoxia-inducible factor-1, integrin β5, endothelial cell specific molecule-1 and intercellular adhesion molecule-1 ( 28 ). Previously, it was demonstrated that TET targets epidermal growth factor receptor signaling and its downstream molecules contribute to the inhibition of epidermal growth factor (EGF)-induced HT29 cell metastasis in vitro ( 29 ). Furthermore, it was also reported that TET-loaded PVP-b-PCL nanoparticles more efficiently inhibit cell migration and invasion compared with free TET in A549 human lung cancer cells ( 30 ).…”