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PJ-34 inhibits PARP-1 expression and ERK phosphorylation in glioma-conditioned brain microvascular endothelial cells.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2015 Aug 15; Vol. 761, pp. 55-64. Date of Electronic Publication: 2015 Apr 28. - Publication Year :
- 2015
-
Abstract
- Inhibitors of PARP-1(Poly(ADP-ribose) polymerase-1) act by competing with NAD(+), the enzyme physiological substrate, which play a protective role in many pathological conditions characterized by PARP-1 overactivation. It has been shown that PARP-1 also promotes tumor growth and progression through its DNA repair activity. Since angiogenesis is an essential requirement for these activities, we sought to determine whether PARP inhibition might affect rat brain microvascular endothelial cells (GP8.3) migration, stimulated by C6-glioma conditioned medium (CM). Through wound-healing experiments and MTT analysis, we demonstrated that PARP-1 inhibitor PJ-34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide] abolishes the migratory response of GP8.3 cells and reduces their viability. PARP-1 also acts in a DNA independent way within the Extracellular-Regulated-Kinase (ERK) signaling cascade, which regulates cell proliferation and differentiation. By western analysis and confocal laser scanning microscopy (LSM), we analyzed the effects of PJ-34 on PARP-1 expression, phospho-ERK and phospho-Elk-1 activation. The effect of MEK (mitogen-activated-protein-kinase-kinase) inhibitor PD98059 (2-(2-Amino-3-methoxyphenyl)-4 H-1-benzopyran-4-one) on PARP-1 expression in unstimulated and in CM-stimulated GP8.3 cells was analyzed by RT-PCR. PARP-1 expression and phospho-ERK activation were significantly reduced by treatment of GP8.3 cells with PJ-34 or PD98059. By LSM, we further demonstrated that PARP-1 and phospho-ERK are coexpressed and share the same subcellular localization in GP8.3 cells, in the cytoplasm as well as in nucleoplasm. Based on these data, we propose that PARP-1 and phospho-ERK interact in the cytosol and then translocate to the nucleus, where they trigger a proliferative response. We also propose that PARP-1 inhibition blocks CM-induced endothelial migration by interfering with ERK signal-transduction pathway.<br /> (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Subjects :
- Active Transport, Cell Nucleus drug effects
Animals
Cell Line, Tumor
Cell Movement drug effects
Endothelial Cells enzymology
Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors
Microvessels enzymology
Phosphorylation
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases genetics
Protein Binding
Protein Kinase Inhibitors pharmacology
Rats
Signal Transduction drug effects
ets-Domain Protein Elk-1 metabolism
Brain blood supply
Brain Neoplasms metabolism
Culture Media, Conditioned metabolism
Endothelial Cells drug effects
Extracellular Signal-Regulated MAP Kinases metabolism
Glioma metabolism
Microvessels drug effects
Paracrine Communication drug effects
Phenanthrenes pharmacology
Poly(ADP-ribose) Polymerase Inhibitors pharmacology
Poly(ADP-ribose) Polymerases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 761
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25934569
- Full Text :
- https://doi.org/10.1016/j.ejphar.2015.04.026