title: Adenosine induces apoptosis through TNFR1/RIPK1/P38 axis in colon cancer cells.
abstract: Adenosine, a metabolite of ATP, ubiquitously exists in a wide range of organs and tissues. We previously reported that adenosine was implicated in apoptosis in many cancer cells by extrinsic and/or intrinsic pathways. Here, we found that adenosine suppresses the cell growth by induction of apoptosis of human colonic cancer cells through a novel mechanism. Adenosine suppresses the cell growth of human SW620 and SW480 colon cells in an adenosine transporter and adenosine kinase dependent manner. Moreover, the cell growth suppression is induced by apoptosis through activation of caspase-3 and PARP, and accumulation of ROS in cells. Importantly, we found that adenosine increases the expression of TNFR1 and RIPK1 and the phosphorylation of p38. Knockdown of TNFR1 or RIPK1 impairs the activation of p38, blocks the cleavage of PARP, and provides partially, yet significantly protection from cell death, including reducing the ROS generation in the colon cancer cells. These results indicate that a TNFR1/RIPK1/P38 axis is present in adenosine-induced apoptosis of colonic cancer cells. This axis triggers apoptosis and plays crucial roles in relay of the death signaling. Our study also provides additional experimental evidence for adenosine as a potent therapeutic drug in cancer therapy.
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.
authors.forename: Shunji
authors.initials: S
authors.lastname: Yu
authors.affiliation: Institutes of Biomedical Sciences and Department of Immunology of Shanghai Medical School, Fudan University, Shanghai 200032, China.
authors.forename: Daisen
authors.initials: D
authors.lastname: Hou
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: 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: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Ma
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: 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: Pennsylvania State University College of Medicine and Hershey Medical Center, Hershey, PA 17033, USA.
authors.forename: Evelyn J
authors.initials: EJ
authors.lastname: Song
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: kobesakura@163.com.
authors.forename: Dongqin
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, 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*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000241:Adenosine
keywords: Adenosine; Apoptosis; RIPK1; TNFR1; p38