Stable depletion of poly (ADP-ribose) polymerase-1 reduces in vivo melanoma growth and increases chemosensitivity.
Poly(ADP-ribose) polymerase (PARP)-1, which plays a key role in DNA repair, inflammation and transcription, has recently been shown to be involved in angiogenesis. The aim of this study was to investigate PARP-1 role in melanoma aggressiveness and chemoresistance in vivo using clones stably silenced for PARP-1 expression. Whilst the growth characteristics of PARP-1-deficient melanoma cells were comparable to those of PARP-1-proficient cells in vitro, their tumourigenic potential in vivo was significantly compromised. In fact, mice challenged intra-muscle with PARP-1-deficient cells showed a delayed development of measurable tumour nodules, which were also significantly reduced in size with respect to those of mice inoculated with PARP-1-proficient cells. Moreover, animals challenged intra-cranially with PARP-1-deficient cells, a model that mimics CNS localisation of melanoma, showed an increased survival. Immunohistochemical analyses of PARP-1-depleted melanoma grafts indicated a reduced expression of the angiogenesis marker PECAM-1/CD31 and of the pro-inflammatory mediators TNF-alpha and GITR. Notably, PARP-1-silenced melanoma was extremely sensitive to temozolomide, an anticancer agent used for the treatment of metastatic melanoma. These results provide novel evidence for a direct role of PARP-1 in tumour aggressiveness and chemoresistance.
Tentori
Lucio
L
Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy.
Muzi
Alessia
A
Dorio
Annalisa Susanna
AS
Bultrini
Stefano
S
Mazzon
Emanuela
E
Lacal
Pedro M
PM
Shah
Girish M
GM
Zhang
Jie
J
Navarra
Pierluigi
P
Nocentini
Giuseppe
G
Cuzzocrea
Salvatore
S
Graziani
Grazia
G
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000502:physiology; D034622:RNA Interference; D014407:Tumor Cells, Cultured
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases