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 Maria
AU - Crinò, Lucio
AU - Peschle, Cesare
AU - De Maria Marchiano, Ruggero
PY - 2005
Y1 - 2005
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. ©2005 American Association for Cancer Research.
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. ©2005 American Association for Cancer Research.
KW - Adult
KW - Aged
KW - Animals
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Apoptosis
KW - Apoptosis Regulatory Proteins
KW - Azacitidine
KW - Cancer Research
KW - Caspase 8
KW - Caspases
KW - DNA Methylation
KW - DNA Modification Methylases
KW - Drug Resistance, Neoplasm
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Glioblastoma
KW - Histocompatibility Antigens Class I
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Male
KW - Membrane Glycoproteins
KW - Mice
KW - Mice, Nude
KW - Middle Aged
KW - Oncology
KW - Phosphoproteins
KW - Receptors, TNF-Related Apoptosis-Inducing Ligand
KW - Receptors, Tumor Necrosis Factor
KW - Signal Transduction
KW - TNF-Related Apoptosis-Inducing Ligand
KW - Transplantation, Heterologous
KW - Tumor Cells, Cultured
KW - Tumor Necrosis Factor-alpha
KW - Adult
KW - Aged
KW - Animals
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Apoptosis
KW - Apoptosis Regulatory Proteins
KW - Azacitidine
KW - Cancer Research
KW - Caspase 8
KW - Caspases
KW - DNA Methylation
KW - DNA Modification Methylases
KW - Drug Resistance, Neoplasm
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Glioblastoma
KW - Histocompatibility Antigens Class I
KW - Humans
KW - Intracellular Signaling Peptides and Proteins
KW - Male
KW - Membrane Glycoproteins
KW - Mice
KW - Mice, Nude
KW - Middle Aged
KW - Oncology
KW - Phosphoproteins
KW - Receptors, TNF-Related Apoptosis-Inducing Ligand
KW - Receptors, Tumor Necrosis Factor
KW - Signal Transduction
KW - TNF-Related Apoptosis-Inducing Ligand
KW - Transplantation, Heterologous
KW - Tumor Cells, Cultured
KW - Tumor Necrosis Factor-alpha
UR - http://hdl.handle.net/10807/113789
U2 - 10.1158/0008-5472.CAN-05-1724
DO - 10.1158/0008-5472.CAN-05-1724
M3 - Article
SN - 0008-5472
VL - 65
SP - 11469
EP - 11477
JO - Cancer Research
JF - Cancer Research
ER -