Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction

Adriana Eramo, Roberto Pallini, Fiorenza Lotti, Giovanni Sette, Mariella Patti, Monica Bartucci, Lucia Ricci-Vitiani, Michele Signore, Giorgio Stassi, Luigi M. Larocca, Lucio Crinò, Cesare Peschle, Ruggero De Maria

Research output: Contribution to journalArticle

Abstract

Life expectancy of patients affected by glioblastoma multiforme is extremely low. The therapeutic use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed to treat this disease based on its ability to kill glioma cell lines in vitro and in vivo. Here, we show that, differently from glioma cell lines, glioblastoma multiforme tumors were resistant to TRAIL stimulation because they expressed low levels of caspase-8 and high levels of the death receptor inhibitor PED/PEA-15. Inhibition of methyltransferases by decitabine resulted in considerable up-regulation of TRAIL receptor-1 and caspase-8, down-regulation of PED/PEA-15, inhibition of cell growth, and sensitization of primary glioblastoma cells to TRAIL-induced apoptosis. Exogenous caspase-8 expression was the main event able to restore TRAIL sensitivity in primary glioblastoma cells. The antitumor activity of decitabine and TRAIL was confirmed in vivo in a mouse model of glioblastoma multiforme. Evaluation of tumor size, apoptosis, and caspase activation in nude mouse glioblastoma multiforme xenografts showed dramatic synergy of decitabine and TRAIL in the treatment of glioblastoma, whereas the single agents were scarcely effective in terms of reduction of tumor mass, apoptosis induction, and caspase activation. Thus, the combination of TRAIL and demethylating agents may provide a key tool to overcome glioblastoma resistance to therapeutic treatments.

Original languageEnglish
Pages (from-to)11469-11477
Number of pages9
JournalCancer Research
Volume65
Issue number24
DOIs
Publication statusPublished - Dec 15 2005

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Eramo, A., Pallini, R., Lotti, F., Sette, G., Patti, M., Bartucci, M., Ricci-Vitiani, L., Signore, M., Stassi, G., Larocca, L. M., Crinò, L., Peschle, C., & De Maria, R. (2005). Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction. Cancer Research, 65(24), 11469-11477. https://doi.org/10.1158/0008-5472.CAN-05-1724