Abstract 4338: The effect of opposing roles of NF-kB on TRAIL-R2 expression in TRAIL cytotoxicity in neuroblastoma cells

Abstract

Abstract TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in most, but not all, cancer cells. The molecular factors regulating the sensitivity to TRAIL are still incompletely understood. The transcription factor nuclear factor-kappa B (NF-kB) has been implicated, but its exact role is controversial. In this study, we have investigated the role of NF-kB on enhancement of TRAIL cytotoxicity in neuroblastoma cells. IkB kinase (IKK) inhibitor decreased basal NF-kB activity and marginally induced cell death in neuroblastoma cell line SK-NMC. Pretreatment with IKK inhibitor synergistically increased TRAIL-mediated apoptosis via up-regulation of TRAIL- receptor2 (TRAIL-R2) expression in response to the decrease in basal NF-kB activity, indicating that basal NF-kB activity blocks TRAIL-R2 expression in SK-NMC cells. In addition, pretreatment with Cisplatin, a platinum analog and an alkylating agent widely used in neuroblstomas, showed increase in NF-kB activity and induction of apoptotic cell death in SK-NMC cells. Pretreatment with Cisplatin significantly increased TRAIL-mediated apoptosis via up-regulation of TRAIL-R2 expression through induction of NF-kB, suggesting that induced NF-kB is involved in TRAIL-R2 expression up-regulated by Cisplatin. IKK inhibitor or Cisplatin followed by TRAIL treatment increased caspase-8, -9, and -3 activation. Mcl-1 cleavage and Bid truncation. Our results implicate that basal NF-kB activity is involved in TRAIL resistance but induced NF-kB plays a role in TRAIL sensitivity, and suggest that the enhanced sensitivity of SK-NMC cells to TRAIL is associated with an increase in TRAIL-R2 expression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4338. doi:10.1158/1538-7445.AM2011-4338