title: Tanshinone IIA inhibits gastric carcinoma AGS cells through increasing p-p38, p-JNK and p53 but reducing p-ERK, CDC2 and cyclin B1 expression.
abstract: Tanshinone IIA (Tan-IIA) is extracted from Danshen (Salviae miltiorrhizae radix). It possesses antitumor activity against a variety of human cancer cells and its induction of apoptosis and inhibition of proliferation of gastric cancer cells are well-documented. However, the molecular mechanisms by which Tan-IIA inhibits gastric cancer have not been well-elucidated. In the present study, we evaluated the cytotoxicity of Tan-IIA against human gastric cancer AGS cells by the (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) MTT assay. The protein expression of tumor necrosis factor-alpha (TNF-α), FAS, p53, p21, cyclin A, cyclin B1, extracellular-related kinase (ERK), phospho extracellular-related kinase (p-ERK), p38, p-p38, Jun-amino-terminal kinase (JNK), phospho Jun-amino-terminal kinase (p-JNK) and β-actin in AGS cells were measured by western blotting. The cell-cycle distribution was analyzed by flow cytometry. The results showed that Tan-IIA inhibited AGS cells with time- and dose-dependent manners. AGS cells treated with Tan-IIA up-regulated the protein expression of TNFα, FAS, p-p38, p-JNK, p53, p21, caspase-3 and caspase-8 but reduced that of p-ERK, CDC2, cyclin A, and cyclin B1. The results also showed that Tan-IIA dose dependently induced G2/M phase arrest. These findings demonstrate that Tan-IIA can inhibit AGS human gastric cancer cells; one of the molecular mechanisms may be through increasing the protein expression of p-p38 and p-JNK, but decreasing that of p-ERK to induce the activation of p53, followed by increasing the protein expression of p21 to down-regulate CDC2 and cyclin B1 expression which then induces G2/M phase arrest. Another route may be through increasing the protein expression of TNF-α, FAS, caspase-8 and caspase-3 to induce apoptosis.
authors.affiliation: Tumor Research Center of Integrative Medicine, Changhua Christian Hospital, Changhua, Taiwan, ROC Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua, Taiwan, ROC Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan, ROC School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, R.O.C. succ.maeva@msa.hinet.net.
authors.forename: Chin-Cheng
authors.initials: CC
authors.lastname: Su
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019925:Cyclin A / Q000096:biosynthesis; D056744:Cyclin B1 / Q000096:biosynthesis; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; D019925:Cyclin A; D056744:Cyclin B1; D010936:Plant Extracts; D016159:Tumor Suppressor Protein p53; C021751:tanshinone; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8
keywords: G2/M arrest; MAPK; Tanshinone IIA; gastric carcinoma AGS cells