TNFAIP3/A20 as a potential regulator of NF-κB-mediated resistance to O6-alkylating chemotherapy in glioblastoma multiforme
Authors: Markus Bredel, Claudia Bredel, Dejan Juric, George Duran, Ron X. Yu, Griffith R. Harsh, Hannes Vogel, Lawrence D. Recht, Adrienne C. Scheck, Branimir I. Sikic
Journal: Cancer Research (2006)

4493   Resistance to chemotherapy is a major obstacle to the successful treatment of glioblastoma multiforme. There is increasing appreciation that drug resistance in tumor cells emerges from the orchestrated activity of multiple cellular components in complex signaling networks. We have utilized an integrated model of glioblastoma resistance to O 6 -alkylating agents (including Temozolomide and BCNU) and genomics tools to globally explore molecular factors, cellular pathways, and functional interaction networks perturbed during the selection and evolution of drug resistance in glioblastoma cells. We have identified a transcriptomic signature of 329 genes that predicts a common  in vitro  and  in vivo  resistance phenotype to these agents (false discovery rate: 0.005), a proportion of which is recurrently imprinted 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 resistance signature, with functions being carried out by groups of interacting molecules in overlapping networks. Our results highlight a key role of a cytoplasmic signaling cascade that activates nuclear factor κB (NF-κB) in response to these agents. Our data indicate the alteration of various members of the NF-κB canonical pathway. Within this pathway, we have identified the tumor necrosis factor α-induced protein 3 (TNFAIP3) gene as a new factor significantly associated with glioblastoma cell resistance. expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was immediately related to NF-κB activation status (nuclear translocation and DNA-binding) in the resistant phenotype. Translation of these findings into the clinic showed that a prediction model based on our cell model-derived resistance signature enabled us to sub-classify an independent validation cohort of 31 glioblastoma patients into distinct outcome groups ( p  = 0.037). We have also revealed TNFAIP3 as part of an optimized four-gene predictor (TNFAIP3, CD44, FBXO32, SDC1) significantly associated with patient survival in glioblastoma multiforme ( p  = 0.022). A Cox proportional-hazards regression analysis of the individual genes in this predictor revealed TNFAIP3 to be significantly associated with outcome when considered as individual continuous variable ( p  = 0.028). Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-κB in the emergence of resistance of glioblastoma cells to O 6 -alkylating chemotherapy. Our observations raise the hope for TNFAIP3 as an amenable target to modulate NF-κB-mediated resistance in these cells, with the ultimate goal of increasing the efficacy of chemotherapy in patients harboring these challenging malignancies.