Interferon-gamma induces caspase-8 in neuroblastomas without affecting methylation of caspase-8 promoter.
BACKGROUND
The expression of caspase-8, a cysteine protease that is crucial for the apoptotic cascade, is absent in a high percentage of neuroblastomas, the most frequent extracranial solid tumor of infants and children. Resistance of neuroblastomas to death-receptor (eg, tumor necrosis factor alpha (TNF-alpha) receptor)--mediated apoptosis is thought to be caused by loss of caspase-8 expression. Gene silencing by hypermethylation of caspase-8 promoter has been proposed for the loss of caspase-8 expression in neuroblastoma cells.


METHODS
To further evaluate the role of caspase-8 in neuroblastoma, we assessed the induction of caspase-8 expression in neuroblastoma cells by treating the cells with a physiologic agent such as interferon-gamma.


RESULTS
The authors found that interferon-gamma induces caspase-8 expression in neuroblastoma cells irrespective of the gene silenced by hypermethylation of caspase-8 promoter. The authors show that interferon-gamma also regulates other apoptosis related gene expression. Moreover, they show that interferon-gamma treatment in combination with TNF-alpha decreases neuroblastoma cell proliferation.


CONCLUSIONS
Interferon-gamma induces procaspase-8 expression in neuroblastoma cells, and this induction is not dependent on demethylation of the caspase-8 promoter. Therapies aimed at inducing caspase-8 expression by adjunctive treatment, such as interferon-gamma, may increase the effectiveness of current chemotherapeutic regimens.
Kim
Sunghoon
S
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0353, USA.
Kang
Junghee
J
Evers
B Mark
BM
Chung
Dai H
DH
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases / Q000096:biosynthesis* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D053938:DNA Fragmentation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases