The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cellsReportar como inadecuado




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Molecular Cancer

, 14:203

First Online: 25 November 2015Received: 20 April 2015Accepted: 18 November 2015DOI: 10.1186-s12943-015-0472-4

Cite this article as: Giannuzzo, A., Pedersen, S.F. & Novak, I. Mol Cancer 2015 14: 203. doi:10.1186-s12943-015-0472-4

Abstract

BackgroundPancreatic ductal adenocarcinoma PDAC is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and-or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one of the ATP receptors, the P2X7 receptor P2X7R could be an important player in PDAC behaviour.

MethodsWe determined the expression real time PCR and Western blot and localization immunofluorescence of P2X7R in human PDAC cell lines AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1 and a -normal- human pancreatic duct epithelial cell line HPDE. The function of P2X7R in proliferation BrdU assay, migration wound assay and invasion Boyden chamber with matrigel was characterized. Furthermore, we studied P2X7R-dependent pore formation YoPro-1 assay and cell death caspase and annexin V - propidium iodide assays.

ResultsWe found higher expression of P2X7R protein in PDAC compared to HPDE cells. P2X7R had notable disparate effects on PDAC survival. Firstly, high concentrations of ATP or the specific P2X7R agonist, BzATP, had cytotoxic effects in all cell lines, and cell death was mediated by necrosis. Moreover, the P2X7R–pore antagonist, A438079, prevented ATP-induced pore formation and cell death. Second, in basal conditions and with low concentrations of ATP-BzATP, the P2X7R allosteric inhibitor AZ10606120 reduced proliferation in all PDAC cell lines. P2X7R also affected other key characteristics of cancer cell behavior. AZ10606120 reduced cell migration and invasion in PDAC cell lines compared to that of untreated-vehicle-treated control cells, and stimulation with sub-millimolar concentrations of ATP or BzATP substantially increased cell invasion.

ConclusionsPDAC cell lines overexpress P2X7R and the receptor plays crucial roles in cell survival, migration and invasion. Therefore, we propose that drugs targeting P2X7R could be exploited in therapy of pancreatic cancer.

KeywordsP2X7 Purinergic signaling Pancreatic ductal adenocarcinoma Pancreatic cancer AZ10606120 KN-62 A438079 Cell proliferation P2Y receptors Electronic supplementary materialThe online version of this article doi:10.1186-s12943-015-0472-4 contains supplementary material, which is available to authorized users.

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Autor: Andrea Giannuzzo - Stine Falsig Pedersen - Ivana Novak

Fuente: https://link.springer.com/



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