Radiation-triggered tumor necrosis factor (TNF) alpha-NFkappaB cross-signaling favors survival advantage in human neuroblastoma cells.

ABSTRACT: Induced radioresistance in the surviving cancer cells after radiotherapy could be associated with clonal selection leading to tumor regrowth at the treatment site. Previously we reported that post-translational modification of I?B? activates NF?B in response to ionizing radiation (IR) and plays a key role in regulating apoptotic signaling. Herein, we investigated the orchestration of NF?B after IR in human neuroblastoma. Both in vitro (SH-SY5Y, SK-N-MC, and IMR-32) and in vivo (xenograft) studies showed that IR persistently induced NF?B DNA binding activity and NF?B-dependent TNF? transactivation and secretion. Approaches including silencing NF?B transcription, blocking post-translational NF?B nuclear import, muting TNF receptor, overexpression, and physiological induction of either NF?B or TNF? precisely demonstrated the initiation and occurrence of NF?B ? TNF? ? NF?B positive feedback cycle after IR that leads to and sustains NF?B activation. Selective TNF-dependent NF?B regulation was confirmed with futile inhibition of AP-1 and SP-1 in TNF receptor muted cells. Moreover, IR increased both transactivation and translation of Birc1, Birc2, and Birc5 and induced metabolic activity and clonal expansion. This pathway was further defined to show that IR-induced functional p65 transcription (not NF?B1, NF?B2, or c-Rel) is necessary for activation of these survival molecules and associated survival advantage. Together, these results demonstrate for the first time the functional orchestration of NF?B in response to IR and further imply that p65-dependent survival advantage and initiation of clonal expansion may correlate with an unfavorable prognosis of human neuroblastoma.

SUBMITTER: Veeraraghavan J 

PROVIDER: S-EPMC3122217 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other