title: Decoy Receptor DcR1 Is Induced in a p50/Bcl3-Dependent Manner and Attenuates the Efficacy of Temozolomide.
abstract: Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53(+/+) glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois.
authors: Nassir M
authors: NM
authors: Mansour
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois.
authors: Giovanna M
authors: GM
authors: Bernal
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois.
authors: Longtao
authors: L
authors: Wu
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois.
authors: Clayton D
authors: CD
authors: Crawley
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois.
authors: Kirk E
authors: KE
authors: Cahill
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois.
authors: David J
authors: DJ
authors: Voce
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois.
authors: Irina V
authors: IV
authors: Balyasnikova
authors: College of Medicine, The University of Illinois at Chicago, Chicago, Illinois.
authors: Wei
authors: W
authors: Zhang
authors: LNK Chemsolutions LLC, Lincoln, Nebraska.
authors: Ruben
authors: R
authors: Spretz
authors: LNK Chemsolutions LLC, Lincoln, Nebraska.
authors: Luis
authors: L
authors: Nunez
authors: LNK Chemsolutions LLC, Lincoln, Nebraska.
authors: Gustavo F
authors: GF
authors: Larsen
authors: Department of Radiation and Cellular Oncology and The Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.
authors: Ralph R
authors: RR
authors: Weichselbaum
authors: Department of Surgery, Section of Neurosurgery, The University of Chicago, Chicago, Illinois. byamini@surgery.bsd.uchicago.edu.
authors: Bakhtiar
authors: B
authors: Yamini
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000081242:B-Cell Lymphoma 3 Protein; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008297:Male; D008819:Mice, Nude; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D000077204:Temozolomide; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D053319:Tumor Necrosis Factor Decoy Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D058851:GPI-Linked Proteins; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; D014157:Transcription Factors; D053319:Tumor Necrosis Factor Decoy Receptors; D003606:Dacarbazine; D000077204:Temozolomide