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 IκBα activates NFκB in response to ionizing radiation (IR) and plays a key role in regulating apoptotic signaling. Herein, we investigated the orchestration of NFκB 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 NFκB DNA binding activity and NFκB-dependent TNFα transactivation and secretion. Approaches including silencing NFκB transcription, blocking post-translational NFκB nuclear import, muting TNF receptor, overexpression, and physiological induction of either NFκB or TNFα precisely demonstrated the initiation and occurrence of NFκB → TNFα → NFκB positive feedback cycle after IR that leads to and sustains NFκB activation. Selective TNF-dependent NFκB 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 NFκB1, NFκB2, 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 NFκB 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.
Highlights
Neuroblastoma (NB),2 the most frequent extra cranial solid tumor in children accounts for 8 –10% of all childhood cancers [1] and 15% of childhood cancer fatalities
ionizing radiation (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 is necessary for activation of these survival molecules and associated survival advantage. These results demonstrate for the first time the functional orchestration of NFB in response to IR and further imply that p65dependent survival advantage and initiation of clonal expansion may correlate with an unfavorable prognosis of human neuroblastoma
We investigated whether the cells of the original neoplasm that have escaped IR insult result in the development of concurrent radioadaptation and survival advantage mediated by persistent activation of NFB through positive feedback (NFB 3 TNF␣ 3 NFB) cycle (PFC)
Summary
Neuroblastoma (NB),2 the most frequent extra cranial solid tumor in children (aged Յ5 years) accounts for 8 –10% of all childhood cancers [1] and 15% of childhood cancer fatalities. Parallel cultures of RelA siRNA transfected SH-SY5Y and IMR-32 cells showed significant inhibition of IR-induced NFB activity (Fig. 2A).
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