CXC chemokine ligand 12 protects pancreatic β-cells from necrosis through Akt kinase-mediated modulation of poly(ADP-ribose) polymerase-1 activity

• Published in: PloS one 2014-07, Vol.9 (7), p.e101172
• Main Authors: Grdović, Nevena, Dinić, Svetlana, Mihailović, Mirjana, Uskoković, Aleksandra, Jovanović, Jelena Arambašić, Poznanović, Goran, Wagner, Ludwig, Vidaković, Melita
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; AKT protein; Animals; Apoptosis; Biology and Life Sciences; Cancer; Cell culture; Cell death; Cell Line, Tumor; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chemokines; CXC chemokines; CXCL12 protein; Cytokines; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Disease control; DNA; Gangrene; Hydrogen; Hydrogen peroxide; Hydrogen Peroxide - adverse effects; Hydrogen Peroxide - pharmacology; Insulin; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Ischemia; Islet cells; Islets of Langerhans; Kinases; Ligands; Male; Medicine and Health Sciences; Modulation; Molecular biology; Mortality; Necrosis; Oxidants - adverse effects; Oxidants - pharmacology; Oxidative stress; Pancreas; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Protein Processing, Post-Translational; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Ribose; Rodents; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101172

The diabetes prevention paradigm envisages the application of strategies that support the maintenance of appropriate β-cell numbers. Herein we show that overexpression of CXC chemokine ligand12 (CXCL12) considerably improves the viability of isolated rat Langerhans islet cells and Rin-5F pancreatic β-cells after hydrogen peroxide treatment. In rat islets and wt cells hydrogen peroxide treatment induced necrotic cell death that was mediated by the rapid and extensive activation of poly(ADP-ribose) polymerase-1 (PARP-1). In contrast, CXCL12-overexpressing cells were protected from necrotic cell death as a result of significantly reduced PARP-1 activity. CXCL12 downstream signalling through Akt kinase was responsible for the reduction of PARP-1 activity which switched cell death from necrosis to apoptosis, providing increased protection to cells from oxidative stress. Our results offer a novel aspect of the CXCL12-mediated improvement of β-cell viability which is based on its antinecrotic action through modulation of PARP-1 activity.