tricetin and Liver-Neoplasms

Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and nobiletin on HGF/c-Met-mediated tumor invasion and metastasis. Among them, nobiletin markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed nobiletin inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, nobiletin could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, nobiletin significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, nobiletin attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma.

Topics: Apigenin; Carcinoma, Hepatocellular; Cell Adhesion; Cell Movement; Cell Survival; Chromones; Flavones; Hep G2 Cells; Hepatocyte Growth Factor; Humans; Liver Neoplasms; Mitogen-Activated Protein Kinase 1; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pseudopodia

This study is the first to investigate the anticancer effect of tricetin (TCN) in two human liver cancer cell lines, Hep G2 and PLC/PRF/5. TCN induced cancer cell death treatment by triggering mitochondrial and death receptor 5 (DR5) apoptotic pathways. Exposure of Hep G2 and PLC/PRF/5 cells to TCN resulted in cellular glutathione reduction and ROS generation, accompanied by JNK activation and apoptosis. Both of the antioxidants vitamin C and catalase significantly decreased apoptosis by inhibiting the phosphorylation of JNK and subsequently triggering DR5 cell death pathways. The reduction of JNK expression by siRNA decreased TCN-mediated Bim cleavage, DR5 up-regulation, and apoptosis. Furthermore, daily TCN intraperitoneal injections in nude mice with PLC/PRF/5 subcutaneous tumors resulted in an approximately 60% decrease of mean tumor volume, compared with vehicle-treated controls. Taken together, the results of the present study indicate that TCN-induced cell death in liver cancer cells is initiated by ROS generation and that both intrinsic and extrinsic apoptotic pathways contribute to the cell death caused by this highly promising cancer chemopreventive agent.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chromones; Flavonoids; Humans; JNK Mitogen-Activated Protein Kinases; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; Xenograft Model Antitumor Assays