MTR-21DECOY RECEPTOR DcR1 IS INDUCED IN A p50/Bcl3-DEPENDENT MANNER AND ATTENUATES THE EFFICACY OF TEMOZOLOMIDE

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INTRODUCTION: Temozolomide (TMZ) is widely used in the management of malignant glioma. Given that almost all patients receive TMZ, resistance to this agent plays a major role in overall patient prognosis. The transcription factor, NF-κB plays an important role in the cytotoxic response to TMZ. To identify novel factors that modulate cytotoxicity, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by TMZ. Decoy receptor 1 (DcR1), a TNF superfamily receptor that blocks apoptosis, was identified as a significantly induced NF-κB-dependent gene. In the current work, we studied DcR1 in response to TMZ. METHODS: DcR1 expression was examined following TMZ treatment by qPCR and western blot in several glioma cells and DcR1 expression studied in public glioma databases. Regulation of DcR1 expression was examined using promoter/reporter, binding and chromatin immunoprecipitation studies. Apoptosis and clonal survival was examined and in vivo studies performed following nanoparticle-mediated delivery of siRNA targeting DcR1. RESULTS: DcR1 is induced by TMZ in an NF-κB and p53-dependent manner with a time course consistent with activation of NF-κB. A conserved NF-κB binding sequence was identified in the proximal promoter and is required for DcR1 induction by TMZ. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by TMZ. Mechanistically, DcR1 attenuates TMZ efficacy by blunting activation of the Fas receptor pathway in p53 wildtype glioma cells. Intracranial xenograft studies demonstrate that DcR1 depletion enhances the efficacy of TMZ and database analyses indicate that patients with higher DcR1 expression have poorer survival. CONCLUSIONS: DcR1 is up-regulated following TMZ treatment and mediates resistance to therapy. These findings provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to TMZ.