Re-expression of caspase-8 in neuroblastoma cells lacking endogenous caspase-8 expression was found to promote cell adhesion to extracellular matrix and to activate adhesion-dependent signaling pathways, such as the Erk kinase cascade.
These data indicate that Fas-mediated apoptosis in neuroblastoma cells is mitochondria-dependent and inhibited both at the mitochondrial level and at the level of caspase 8 activation.
These data indicate that the pattern of expression of these neural-enriched IG20-SVs regulates the expression and activation of caspase-8 in certain neuroblastoma cells, and that manipulation of IG20-SV expression pattern may represent a potent therapeutic strategy in the therapy of neuroblastoma and perhaps other cancers.
We established N-myc-downregulated IMR-32 cells using shRNA lentiviral particles targeting N-myc and examined the effect the N-myc inhibition on TRAIL susceptibility in human neuroblastoma IMR-32 cells expressing caspase-8.
The combined data suggest that FOXO3 is activated by 5-azadC treatment and triggers expression of caspase-8 in caspase-8-negative neuroblastoma, which may have important implication for metastasis, therapy, and death resistance of this childhood malignancy.
Thus, by demonstrating that 5-dAzaC and IFN-gamma at relatively low individual concentrations cooperate to restore caspase-8 expression and sensitize resistant neuroblastoma and medulloblastoma cells to TRAIL-induced apoptosis, our findings have important implications for novel strategies targeting defective apoptosis pathways in neuroectodermal tumors.
We investigated whether the levels of survivin and caspase 8 and the ratio between these 2 apoptotic factors correlate with tumor biology and predicts outcome in patients with neuroblastoma.
We sought to determine whether caspase 8l is present in neuroblastoma and whether over-expression of this protein could inhibit caspase 8-dependent apoptosis.
These results indicate that the profile of caspase 8 expression is an important determinant of the response of neuroblastoma cells to Fas-mediated cell death.
Thus, by demonstrating that 5-dAzaC and IFN-gamma at relatively low individual concentrations cooperate to restore caspase-8 expression and sensitize resistant neuroblastoma and medulloblastoma cells to TRAIL-induced apoptosis, our findings have important implications for novel strategies targeting defective apoptosis pathways in neuroectodermal tumors.
Exogenous interferon-γ upregulated expression of caspase-8 in 3 of 4 neuroblastoma cell lines and increased the contribution of TRAIL to NK cytotoxicity against 2 of the 3 lines; however, relatively little inhibition of cytotoxicity was observed when activated NK cells were treated with an anti-interferon-γ neutralizing antibody.
A missense mutation was detected at codon 96, GCT (Alanine) to GTT (Valine), of the caspase 8 gene in one of the NB cell lines lacking caspase 8 expression.
The authors found that interferon-gamma induces caspase-8 expression in neuroblastoma cells irrespective of the gene silenced by hypermethylation of caspase-8 promoter.
By revealing no correlation between caspase-8 expression and MYCN amplification or other established variables of aggressive disease, our findings in a large cohort of neuroblastoma patients show that inactivation of caspase-8 is not a characteristic feature of aggressive neuroblastoma.
Subcellular fractionation analysis revealed caspase-8 activity in both cytosol and plasma membrane fractions in both NB7 reconstituted caspase-8 cell lines, as well the LNCaP prostate cancer cells.
Our results show that restoration of active caspase-8 expression in a caspase-8-deficient NB cell line is necessary and sufficient to fully restore TRAIL sensitivity.
Here we show that four different retinoic acid (RA) derivatives also increase caspase-8 protein expression in neuroblastoma, medulloblastoma and small cell lung carcinoma cell lines.
However, approximately 20% of the neuroblastoma cell lines with methylated CASP8 alleles are also highly resistant to staurosporine (STS)- and radiation-induced cell death, presumably because cytochrome c is not released from mitochondria.
DNA derived from 70 neuroblastomas was amplified by PCR after bisulfate modification and subjected to analysis on a self-made oligoarray that utilized a polycarbodiimide-coated slide to detect methylation of six intragenic CpG islands of caspase 8.