title: Induction of hepatoma carcinoma cell apoptosis through activation of the JNK-nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-ROS self-driven death signal circuit.
abstract: As an efficient method for inducing tumor cell apoptosis, ROS can be constantly formed and accumulated in NADPH oxidase overactivated-cells, resulting in further mitochondrial membrane damage and mitochondria-dependent apoptosis. In addition, JNK mitogen-activated protein kinase (JNK MAPK) signal also acts as a vital candidate pathway for inducing tumor cell apoptosis by targeting mitochondrial death pathway. However, the relationship between NADPH oxidase-ROS and JNK MAPK signal still remains unclear. Here, we discovered a novel self-driven signal circuit between NADPH oxidase-ROS and JNK MAPK, which was induced by a cytotoxic steroidal saponin (ASC) in hepatoma carcinoma cells. NADPH oxidase-dependent ROS production was markedly activated by ASC and directly led to JNK MAPK activation. Moreover, antioxidant, NADPH oxidase inhibitor and specific knock-out for p47 subunit of NADPH oxidase could effectively block NADPH oxidase-ROS-dependent JNK activation, suggesting that NADPH oxidase is an upstream regulator of JNK MAPK. Conversely, a specific JNK inhibitor could inhibit ASC-induced NADPH oxidase activation and down-regulate ROS levels as well, indicating that JNK might also regulate NADPH oxidase activity to some extent. These observations indicate that NADPH oxidase and JNK MAPK activate each other as a signal circuit. Furthermore, drug pretreatment experiments with ASC showed this signal circuit operated continuously via a self-driven mode and finally induced apoptosis in hepatoma carcinoma cells. Taken together, we provide a proof for inducing hepatoma carcinoma cell apoptosis by activating the JNK-NADPH oxidase-ROS-dependent self-driven signal circuit pathway.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Ke-Wu
authors: KW
authors: Zeng
authors: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing 100034, China.
authors: Fang-Jiao
authors: FJ
authors: Song
authors: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing 100034, China.
authors: Ying-Hong
authors: YH
authors: Wang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Ning
authors: N
authors: Li
authors: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing 100034, China.
authors: Qian
authors: Q
authors: Yu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Li-Xi
authors: LX
authors: Liao
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Yong
authors: Y
authors: Jiang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: pengfeitu@vip.163.com.
authors: Peng-Fei
authors: PF
authors: Tu
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular; D002470:Cell Survival; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms; D020935:MAP Kinase Signaling System; D053078:Membrane Potential, Mitochondrial; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: JNK MAPK; NADPH oxidase; Reactive oxygen species; Self-driven signal circuit