TY - JOUR
T1 - Aggressive childhood neuroblastomas do not express caspase-8
T2 - An important component of programmed cell death
AU - Teitz, Tal
AU - Lahti, Jill M.
AU - Kidd, Vincent J.
N1 - Funding Information:
Acknowledgements The authors thank Tie Wei, Jose Grenet, Marcus B. Valentine, Virginia A. Valentine, Elio F. Vanin, A. Thomas Look, and Frederick G. Behm for their contributions to the studies highlighted in this article. This work was supported by National Institutes of Health grants CA 67938, a Cancer Center Core grant from the National Institutes of health to St. Jude Children’s Research Hospital (CA 21765), and by support from the American Lebanese Syrian Associated Charities.
PY - 2001
Y1 - 2001
N2 - Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation, to identify tumor suppressor genes in this group of neuroblastomas we analyzed the expression and function of both apoptosis-related cell cycle regulatory genes in cell lines and patient tumor samples. We found that in a high percentage of neuroblastoma cell lines and patient samples with amplified MYCN, caspase-8 mRNA is not expressed. The caspase-8 gene, CASP8, was deleted or silenced by methylation in the neuroblastoma cell lines while methylation of its promoter region was the predominant mechanism for its inactivation in the patient tumor samples. Reintroduction of caspase-8 into the neuroblastoma cell lines resensitized these cells to drug-induced and survival factor dependent apoptosis. Subsequently others have also shown that caspase-8 is silenced by methylation in neuroblastoma and peripheral neural ectodermal tumors, and that the caspase-9 regulator Apaf-1 is silenced by methylation in melanoma cell lines and patient samples. We conclude that caspase-8 acts as a tumor suppressor gene in neuroblastomas, that its silencing provides a permissive environment for MYCN gene amplification once the tumors are treated with chemotherapeutic drugs/irradiation, and that expression of this gene in these tumor cells may be of clinical benefit. We also discuss the possible significance of the neural crest cell progenitor cell origin and the silencing of important apoptotic regulators via methylation in both neuroblastoma and melanoma tumors.
AB - Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation, to identify tumor suppressor genes in this group of neuroblastomas we analyzed the expression and function of both apoptosis-related cell cycle regulatory genes in cell lines and patient tumor samples. We found that in a high percentage of neuroblastoma cell lines and patient samples with amplified MYCN, caspase-8 mRNA is not expressed. The caspase-8 gene, CASP8, was deleted or silenced by methylation in the neuroblastoma cell lines while methylation of its promoter region was the predominant mechanism for its inactivation in the patient tumor samples. Reintroduction of caspase-8 into the neuroblastoma cell lines resensitized these cells to drug-induced and survival factor dependent apoptosis. Subsequently others have also shown that caspase-8 is silenced by methylation in neuroblastoma and peripheral neural ectodermal tumors, and that the caspase-9 regulator Apaf-1 is silenced by methylation in melanoma cell lines and patient samples. We conclude that caspase-8 acts as a tumor suppressor gene in neuroblastomas, that its silencing provides a permissive environment for MYCN gene amplification once the tumors are treated with chemotherapeutic drugs/irradiation, and that expression of this gene in these tumor cells may be of clinical benefit. We also discuss the possible significance of the neural crest cell progenitor cell origin and the silencing of important apoptotic regulators via methylation in both neuroblastoma and melanoma tumors.
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U2 - 10.1007/s001090100233
DO - 10.1007/s001090100233
M3 - Article
C2 - 11511973
AN - SCOPUS:0034886497
VL - 79
SP - 428
EP - 436
JO - Clinical Investigator
JF - Clinical Investigator
SN - 0946-2716
IS - 8
ER -