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

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

Research output: Contribution to journalArticle

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-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.

Original languageEnglish (US)
Pages (from-to)1302-1314
Number of pages13
JournalEuropean Journal of Cancer
Volume44
Issue number9
DOIs
StatePublished - Jun 2008
Externally publishedYes

Keywords

  • Angiogenesis
  • Melanoma
  • Poly(ADP-ribose) polymerase
  • Temozolomide

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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  • Cite this

    Tentori, L., Muzi, A., Dorio, A. S., Bultrini, S., Mazzon, E., Lacal, P. M., Shah, G. M., Zhang, J., Navarra, P., Nocentini, G., Cuzzocrea, S., & Graziani, G. (2008). Stable depletion of poly (ADP-ribose) polymerase-1 reduces in vivo melanoma growth and increases chemosensitivity. European Journal of Cancer, 44(9), 1302-1314. https://doi.org/10.1016/j.ejca.2008.03.019