title: Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas.
abstract: OBJECTIVE
  Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas.
  
  
  METHODS
  We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells.
  
  
  RESULTS
  We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-kappaB (NF-kappaB), which included the persistent alterations of various NF-kappaB pathway elements. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-kappaB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-kappaB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022).
  
  
  CONCLUSIONS
  Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-kappaB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.
authors.affiliation: Division of Oncology, Center for Clinical Sciences Research, Institute for Computational and Mathematical Engineering, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5151, USA. mbredel@stanford.edu
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
authors.forename: Claudia
authors.initials: C
authors.lastname: Bredel
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.forename: George E
authors.initials: GE
authors.lastname: Duran
authors.forename: Ron X
authors.initials: RX
authors.lastname: Yu
authors.forename: Griffith R
authors.initials: GR
authors.lastname: Harsh
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Recht
authors.forename: Adrienne C
authors.initials: AC
authors.lastname: Scheck
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D018628:Gene Dosage; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D000077204:Temozolomide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D003606:Dacarbazine; D004247:DNA; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D002330:Carmustine; D000077204:Temozolomide