MycN and IFNγ cooperate in apoptosis of human neuroblastoma cells

Abstract

Neuroblastomas undergo spontaneous regression at an unusually high rate. The mechanisms are not clear, but apoptosis may be involved. A large proportion of neuroblastomas is characterized by amplification of MYCN. Using human neuroblastoma cells harbouring tetracycline controlled expression of MYCN we have analysed the role of the MycN protein and IFNγ in cell death decision. Neither conditional expression of MYCN nor treatment with IFNγ alone was sufficient to trigger cell death. However, when acting in concert MycN and IFNγ efficiently triggered cell death, which was accompanied by DNA fragmentation and required caspase activity, two hallmarks of apoptosis. MycN and IFNγ may cooperate along at least two different pathways. First, IFNγ increased the CD95 cell surface expression while MycN enhanced the cellular susceptibility for the CD95 mediated death signal. Second, IFNγ treatment induced expression of BAK mRNA while MycN and IFNγ in combination increased the amount of Bax protein, another activator of apoptosis, without a concomitant increase in BAX mRNA. MycN also increased cell death in response to TRAIL and TNFα, suggesting that enforced MYCN expression in general increases the susceptibility of neuroblastoma cells towards a variety of death stimuli.