title: Adenosine induces apoptosis in human liver cancer cells through ROS production and mitochondrial dysfunction.
abstract: Mitochondria are the most important sensor for apoptosis. Extracellular adenosine is well reported to induce apoptosis of tumor cells. Here we found that extracellular adenosine suppresses the cell growth by induction of apoptosis in BEL-7404 liver cancer cells, and identified a novel mechanism that extracellular adenosine triggers apoptosis by increasing Reactive Oxygen Species (ROS) production and mitochondrial membrane dysfunction in the cells. We observed that adenosine increases ROS production, activates c-Caspase-8 and -9 and Caspase effectors, c-Caspase-3 and c-PARP, induces accumulation of apoptosis regulator Bak, decreases Bcl-xL and Mcl-1, and causes the mitochondrial membrane dysfunction and the release of DIABLO, Cytochrome C, and AIF from mitochondria to cytoplasm in the cells; ROS inhibitor, NAC significantly reduces adenosine-induced ROS production; it also shows the same degree of blocking adenosine-induced loss of mitochondrial membrane potential (MMP) and apoptosis. Our study first observed that adenosine increases ROS production in tumor cells and identified the positive feedback loop for ROS-mediated mitochondrial membrane dysfunction which amplifies the death signals in the cells. Our findings indicated ROS production and mitochondrial dysfunction play a key role in adenosine-induced apoptosis of 7404 cells.
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institutes of Biomedical Sciences and Department of Immunology of Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institutes of Biomedical Sciences and Department of Immunology of Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Junyao
authors.initials: J
authors.lastname: Song
authors.affiliation: Institutes of Biomedical Sciences and Department of Immunology of Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Shunji
authors.initials: S
authors.lastname: Yu
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
authors.forename: Fuchen
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: yang.10079@hotmail.com.
authors.forename: Dongqin
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences and Department of Immunology of Shanghai Medical School, Fudan University, Shanghai 200032, China. Electronic address: jieliu@fudan.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D020169:Caspases; D000241:Adenosine
keywords: Adenosine; Apoptosis; BEL-7404; MMP; ROS