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

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Karaçay B., Sanlioglu S., GRIFFITH T., SANDLER A., BONTHIUS D.

CANCER GENE THERAPY, cilt.11, sa.10, ss.681-690, 2004 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 11 Sayı: 10
  • Basım Tarihi: 2004
  • Doi Numarası: 10.1038/sj.cgt.7700749
  • Dergi Adı: CANCER GENE THERAPY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.681-690
  • Anahtar Kelimeler: neuroblastoma, TRAIL, NF-kappa B, IKK beta dominant-negative mutant, apoptosis, TRANSCRIPTION FACTOR, ANNEXIN-V, EXPRESSION, PHOSPHATIDYLSERINE, CANCER, DEATH, RECEPTORS, GENE, ACTIVATION, RESISTANCE
  • Akdeniz Üniversitesi Adresli: Evet

Özet

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.