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

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.
AuthorsShu Bian, Xiaofeng Sun, Aiping Bai, Chunqing Zhang, Linglin Li, Keiichi Enjyoji, Wolfgang G Junger, Simon C Robson, Yan Wu
JournalPloS one (PLoS One) Vol. 8 Issue 4 Pg. e60184 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23565201 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Phosphoproteins
  • Receptors, Purinergic P2X7
  • proline-rich Akt substrate, 40 kDa protein, mouse
  • Adenosine Triphosphate
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Proto-Oncogene Proteins c-akt
  • AMP-Activated Protein Kinases (metabolism)
  • Adenosine Triphosphate (pharmacology)
  • Animals
  • Calcium Signaling (drug effects)
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Gene Knockdown Techniques
  • Male
  • Mice
  • Models, Biological
  • Neoplasms (genetics, metabolism)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphoproteins (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Receptors, Purinergic P2X7 (genetics, metabolism)
  • Signal Transduction (drug effects)
  • TOR Serine-Threonine Kinases (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: