title: Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53.
abstract: Tumor cells undergo changes in metabolism to meet their energetic and anabolic needs. It is conceivable that mechanisms exist to sense these changes and link them to pathways that eradicate cells primed for cancer development. We report that the tumor suppressor p53 activates a cell death priming mechanism that senses extracellular adenosine. Adenosine, the backbone of ATP, accumulates under conditions of cellular stress or altered metabolism. We show that its receptor, A2B, is upregulated by p53. A2B expression has little effect on cell viability, but ligand engagement activates a caspase- and Puma-dependent apoptotic response involving downregulation of antiapoptotic Bcl-2 proteins. Stimulation of A2B also significantly enhances cell death mediated by p53 and upon accumulation of endogenous adenosine following chemotherapeutic drug treatment and exposure to hypoxia. Since extracellular adenosine also accumulates within many solid tumors, this distinct p53 function links programmed cell death to both a cancer- and therapy-associated metabolic change.
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Long
authors.forename: Diane
authors.initials: D
authors.lastname: Crighton
authors.forename: James
authors.initials: J
authors.lastname: O'Prey
authors.forename: Gillian
authors.initials: G
authors.lastname: Mackay
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Palmer
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Ryan
mesh_terms: D000241:Adenosine / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D043704:Receptor, Adenosine A2B; D016159:Tumor Suppressor Protein p53; D020169:Caspases; D000241:Adenosine