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

60 Citations (Scopus)

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

Fingerprint

DNA Methylation
Glioblastoma
decitabine
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Caspase 8
Caspases
Glioma
TNF-Related Apoptosis-Inducing Ligand Receptors
Cell Line
Neoplasms
Death Domain Receptors
Methyltransferases
Therapeutic Uses
Life Expectancy
Heterografts
Nude Mice
Up-Regulation
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction. / Eramo, Adriana; Pallini, Roberto; Lotti, Fiorenza; Sette, Giovanni; Patti, Mariella; Bartucci, Monica; Ricci-Vitiani, Lucia; Signore, Michele; Stassi, Giorgio; Larocca, Luigi M.; Crinò, Lucio; Peschle, Cesare; De Maria, Ruggero.

In: Cancer Research, Vol. 65, No. 24, 15.12.2005, p. 11469-11477.

Research output: Contribution to journalArticle

Eramo, A, Pallini, R, Lotti, F, Sette, G, Patti, M, Bartucci, M, Ricci-Vitiani, L, Signore, M, Stassi, G, Larocca, LM, 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, vol. 65, no. 24, pp. 11469-11477. https://doi.org/10.1158/0008-5472.CAN-05-1724
Eramo, Adriana ; Pallini, Roberto ; Lotti, Fiorenza ; Sette, Giovanni ; Patti, Mariella ; Bartucci, Monica ; Ricci-Vitiani, Lucia ; Signore, Michele ; Stassi, Giorgio ; Larocca, Luigi M. ; Crinò, Lucio ; Peschle, Cesare ; De Maria, Ruggero. / Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction. In: Cancer Research. 2005 ; Vol. 65, No. 24. pp. 11469-11477.
@article{5aa5baba59674050aa874c84ad990a2c,
title = "Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction",
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.",
author = "Adriana Eramo and Roberto Pallini and Fiorenza Lotti and Giovanni Sette and Mariella Patti and Monica Bartucci and Lucia Ricci-Vitiani and Michele Signore and Giorgio Stassi and Larocca, {Luigi M.} and Lucio Crin{\`o} and Cesare Peschle and {De Maria}, Ruggero",
year = "2005",
month = "12",
day = "15",
doi = "10.1158/0008-5472.CAN-05-1724",
language = "English",
volume = "65",
pages = "11469--11477",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

TY - JOUR

T1 - Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction

AU - Eramo, Adriana

AU - Pallini, Roberto

AU - Lotti, Fiorenza

AU - Sette, Giovanni

AU - Patti, Mariella

AU - Bartucci, Monica

AU - Ricci-Vitiani, Lucia

AU - Signore, Michele

AU - Stassi, Giorgio

AU - Larocca, Luigi M.

AU - Crinò, Lucio

AU - Peschle, Cesare

AU - De Maria, Ruggero

PY - 2005/12/15

Y1 - 2005/12/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=29244477848&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29244477848&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-1724

DO - 10.1158/0008-5472.CAN-05-1724

M3 - Article

VL - 65

SP - 11469

EP - 11477

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 24

ER -