Inhibition of the NF-kappaB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells.
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-kappaB (NF-kappaB) signaling pathway, which can exert an antiapoptotic effect, we hypothesized that inhibition of NF-kappaB 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 IkappaB kinase, a kinase essential for NF-kappaB activation. The combination of blockade of NF-kappaB 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-kappaB pathway and the induction of TRAIL-mediated apoptosis may become a useful approach for the treatment of neuroblastoma.
Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA. bahri-karacay@uiowa.edu
Bahri
B
Karacay
Salih
S
Sanlioglu
Thomas S
TS
Griffith
Anthony
A
Sandler
Daniel J
DJ
Bonthius
D000256:Adenoviridae / Q000235:genetics; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051550:I-kappa B Kinase; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
D017304:Annexin A5; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human