Neuroblastoma is the most common solid extracranial neoplasm in children and causes many deaths. Despite treatment advances, prognosis for neuroblastoma remains poor, and a critical need exists for the development of new treatment regimens. TNF-related apoptosis-inducing-ligand (TRAIL) induces cell death in a variety of tumors, but not in normal tissues. Moreover, TRAIL is nontoxic, making it a strong antitumor therapeutic candidate. We demonstrate that introduction of the TRAIL gene into neuroblastoma cell lines using an adenoviral vector leads to apoptotic cell death. RT-PCR and flow-cytometric analyses demonstrated that TRAIL's effect is mediated primarily via the TRAIL R2 receptor. As TRAIL can activate the nuclear factor-κB (NF-κB) signaling pathway, which can exert an antiapoptotic effect, we hypothesized that inhibition of NF-κB signaling may augment TRAIL's killing effects. TRAIL-mediated cell death was enhanced when neuroblastoma cells were simultaneously infected with a dominant-negative mutant of IκB kinase, a kinase essential for NF-κB activation. The combination of blockade of NF-κB signaling and expression of TRAIL induced apoptotic death in a greater proportion of SKNSH cells than did either treatment alone. Thus, concurrent inhibition of the NF-κB pathway and the induction of TRAIL-mediated apoptosis may become a useful approach for the treatment of neuroblastoma.
Bibliographical noteFunding Information:
This work was supported by Grants from the Children’s Miracle Network (to BK), Akdeniz University Scientific Research Division Administration (to SS), and National Cancer Institute, Holden Comprehensive Cancer Center of the University of Iowa, and Howard Hughes Medical Research Institute Collaborative Grant (to DJB).
- IKKβ dominant-negative mutant