NF-?B regulates caspase-4 expression and sensitizes neuroblastoma cells to Fas-induced apoptosis.
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ABSTRACT: Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-?B signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-?B activation in Fas killing and the effect of NF-?B activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-?B signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-?B activation was shown to be pro-apoptotic, as suggested by the reduction of Fas-induced cell death with either a dominant negative form of I?B? (DN-I?B?) or an I?B kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-?B signaling, we found that DN-I?B? only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-?B activity by p65 (RelA) overexpression increased the expression of caspase-4 at both mRNA and protein levels. More directly, results from dual luciferase reporter assay demonstrated the regulation of caspase-4 promoter activity by NF-?B. When caspase-4 activity was blocked by its dominant negative (DN) form, Fas-induced cell death was substantially reduced. Consistently, the cleavage of PARP and caspase-3 induced by Fas was also reduced. In contrast, the cleavage of caspase-8 remained unaffected in caspase-4 DN cells, although caspase-8 inhibitor could rescue Fas-induced cell death. Collectively, these data suggest that caspase-4 activity is required for Fas-induced cell apoptosis and caspase-4 may act upstream of PARP and caspase-3 and downstream of caspase-8. Overall, we demonstrate that NF-?B can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-?B pro-apoptotic pathway in neuroblastoma cells.
SUBMITTER: Yang HJ
PROVIDER: S-EPMC4335045 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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