Stable depletion of poly (ADP-ribose) polymerase-1 reduces in vivo melanoma growth and increases chemosensitivity.

Pierluigi Navarra, Alessia Muzi, Lucio Tentori, Annalisa Susanna Dorio, Stefano Bultrini, Emanuela Mazzon, Pedro M. Lacal, Girish M. Shah, Jie Zhang, Giuseppe Nocentini, Salvatore Cuzzocrea, Grazia Graziani

Risultato della ricerca: Contributo in rivistaArticolo in rivista

37 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)1302-1314
Numero di pagine13
RivistaEuropean Journal of Cancer
Stato di pubblicazionePubblicato - 2008

Keywords

  • Melanoma
  • PARP-1

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