NF-kappaB regulates caspase-4 expression and sensitizes neuroblastoma cells to Fas-induced apoptosis.
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Yang HJ, Wang M, Wang L, Cheng BF, Lin XY, Feng ZW
NF-kappaB regulates caspase-4 expression and sensitizes neuroblastoma cells to Fas-induced apoptosis.
PLoS One. 2015 Feb 19;10(2):e0117953. doi: 10.1371/journal.pone.0117953. eCollection 2015.
- PubMed ID
- 25695505 [ View in PubMed]
- Abstract
Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-kappaB signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-kappaB activation in Fas killing and the effect of NF-kappaB activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-kappaB signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-kappaB activation was shown to be pro-apoptotic, as suggested by the reduction of Fas-induced cell death with either a dominant negative form of IkappaBalpha (DN-IkappaBalpha) or an IkappaB kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-kappaB signaling, we found that DN-IkappaBalpha only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-kappaB 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-kappaB. 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-kappaB can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-kappaB pro-apoptotic pathway in neuroblastoma cells.