TY - JOUR
T1 - Stable depletion of poly (ADP-ribose) polymerase-1 reduces in vivo melanoma growth and increases chemosensitivity
AU - Tentori, Lucio
AU - Muzi, Alessia
AU - Dorio, Annalisa Susanna
AU - Bultrini, Stefano
AU - Mazzon, Emanuela
AU - Lacal, Pedro M.
AU - Shah, Girish M.
AU - Zhang, Jie
AU - Navarra, Pierluigi
AU - Nocentini, Giuseppe
AU - Cuzzocrea, Salvatore
AU - Graziani, Grazia
PY - 2008/6
Y1 - 2008/6
N2 - 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-α 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.
AB - 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-α 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.
KW - Angiogenesis
KW - Melanoma
KW - Poly(ADP-ribose) polymerase
KW - Temozolomide
UR - http://www.scopus.com/inward/record.url?scp=44449115048&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44449115048&partnerID=8YFLogxK
U2 - 10.1016/j.ejca.2008.03.019
DO - 10.1016/j.ejca.2008.03.019
M3 - Article
C2 - 18440222
AN - SCOPUS:44449115048
SN - 0959-8049
VL - 44
SP - 1302
EP - 1314
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 9
ER -