P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death

• Published in: PloS one Vol. 8; no. 4; p. e60184
• Main Authors: Bian, Shu, Sun, Xiaofeng, Bai, Aiping, Zhang, Chunqing, Li, Linglin, Enjyoji, Keiichi, Junger, Wolfgang G, Robson, Simon C, Wu, Yan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.04.2013; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenosine triphosphate; Adenosine Triphosphate - pharmacology; AKT protein; AMP-Activated Protein Kinases - metabolism; Animals; Antitumor activity; Apoptosis; ATP; ATP (Adenosine triphosphate); Autophagy; Biology; Calcium Signaling - drug effects; Cancer; Cancer therapies; Cell death; Cell Death - drug effects; Cell growth; Cell Line, Tumor; Cell survival; Chronic exposure; Cytotoxicity; Drugs; Exposure; Gastroenterology; Gene Knockdown Techniques; Hazards; Health aspects; Immunity; Immunotherapy; In vivo methods and tests; Intracellular signalling; Kinases; Male; Medical schools; Medicine; Mice; Models, Biological; Molecular modelling; Mortality; Neoplasms - genetics; Neoplasms - metabolism; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Prostate cancer; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism; Risk factors; Signal transduction; Signal Transduction - drug effects; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor cell lines; Tumor cells; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060184

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. 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. 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.