The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells
| Autor: | Andrea Giannuzzo, Ivana Novak, Stine F. Pedersen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
endocrine system diseases P2Y receptors Pyridines Tetrazoles Adamantane Apoptosis KN-62 Pancreatic ductal adenocarcinoma chemistry.chemical_compound Adenosine Triphosphate Cell Movement Cell proliferation Caspase 7 Caspase 3 Purinergic signaling Cell migration 3. Good health Oncology Aminoquinolines Molecular Medicine P2X7 Carcinoma Pancreatic Ductal medicine.medical_specialty Stromal cell Purinergic P2X Receptor Antagonists Cell Survival Biology AZ10606120 Purinergic P2X Receptor Agonists Internal medicine Pancreatic cancer Cell Line Tumor medicine Humans Neoplasm Invasiveness Propidium iodide A438079 Matrigel Cell growth Research medicine.disease digestive system diseases Pancreatic Neoplasms Endocrinology chemistry Cancer cell Cancer research Receptors Purinergic P2X7 |
| Zdroj: | Molecular Cancer Giannuzzo, A, Pedersen, S H F & Novak, I 2015, ' The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells ', Molecular Cancer, vol. 14, 203 . https://doi.org/10.1186/s12943-015-0472-4 |
| ISSN: | 1476-4598 |
| DOI: | 10.1186/s12943-015-0472-4 |
| Popis: | Background Pancreatic 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. Methods We 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). Results We 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. Conclusions PDAC 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. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0472-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink