title: P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death.
abstract: BACKGROUND
  Extracellular adenosine triphosphate (ATP) functions as a novel danger signal that boosts antitumor immunity and can also directly kill tumor cells. We have previously reported that chronic exposure of tumor cells to ATP provokes P2X7-mediated tumor cell death, by as yet incompletely defined molecular mechanisms.
  
  
  RESULTS
  Here, we show that acute exposure of tumor cells to ATP results in rapid cytotoxic effects impacting several aspects of cell growth/survival, leading to inhibition of tumor growth in vitro and in vivo. Using agonist and antagonist studies together with generation of P2X7 deficient tumor cell lines by lentiviral shRNA delivery system, we confirm P2X7 to be the central control node transmitting extracellular ATP signals. We identify that downstream intracellular signaling regulatory networks implicate two signaling pathways: the known P2X7-PI3K/AKT axis and remarkably a novel P2X7-AMPK-PRAS40-mTOR axis. When exposed to high levels of extracellular ATP, these two signaling axes perturb the balance between growth and autophagy, thereby promoting tumor cell death.
  
  
  CONCLUSIONS
  Our study defines novel molecular mechanisms underpinning the antitumor actions of P2X7 and provides a further rationale for purine-based drugs in targeted cancer therapy.
authors.affiliation: Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Bian
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Sun
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.forename: Chunqing
authors.initials: C
authors.lastname: Zhang
authors.forename: Linglin
authors.initials: L
authors.lastname: Li
authors.forename: Keiichi
authors.initials: K
authors.lastname: Enjyoji
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D058486:Receptors, Purinergic P2X7; D058570:TOR Serine-Threonine Kinases; C508191:proline-rich Akt substrate, 40 kDa protein, mouse
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