Inhibition of the NF-kappaB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells

Bahri Karacay; Salih Sanlioglu; Thomas S Griffith; Anthony Sandler; Daniel J Bonthius

doi:10.1038/sj.cgt.7700749

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Inhibition of the NF-kappaB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells

Journal article

Peer reviewed

Inhibition of the NF-kappaB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells

Bahri Karacay, Salih Sanlioglu, Thomas S Griffith, Anthony Sandler and Daniel J Bonthius

Cancer gene therapy, Vol.11(10), pp.681-690

10/2004

DOI: 10.1038/sj.cgt.7700749

PMID: 15332116

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Abstract

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.

Flow Cytometry

Gene Expression

Genetic Therapy

Apoptosis - drug effects

Humans

Tumor Necrosis Factor-alpha - genetics

NF-kappa B - metabolism

RNA, Messenger - metabolism

Receptors, TNF-Related Apoptosis-Inducing Ligand

TNF-Related Apoptosis-Inducing Ligand

Protein-Serine-Threonine Kinases - antagonists & inhibitors

Adenoviridae - genetics

Neuroblastoma - pathology

Receptors, Tumor Necrosis Factor - metabolism

NF-kappa B - antagonists & inhibitors

Membrane Glycoproteins - pharmacology

Recombinant Proteins - pharmacology

I-kappa B Kinase

Reverse Transcriptase Polymerase Chain Reaction

Membrane Glycoproteins - genetics

Tumor Necrosis Factor-alpha - pharmacology

Annexin A5 - metabolism

Apoptosis Regulatory Proteins

Cell Line, Tumor

Neuroblastoma - metabolism

Genetic Vectors

Details

Title: Subtitle: Inhibition of the NF-kappaB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells
Creators: Bahri Karacay - Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA. bahri-karacay@uiowa.edu
Salih Sanlioglu
Thomas S Griffith
Anthony Sandler
Daniel J Bonthius
Resource Type: Journal article
Publication Details: Cancer gene therapy, Vol.11(10), pp.681-690
Publisher: England
DOI: 10.1038/sj.cgt.7700749
PMID: 15332116
ISSN: 0929-1903
eISSN: 1476-5500
Language: English
Date published: 10/2004
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984071709902771

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