title: Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death.
abstract: Inhibitor of apoptosis (IAP) proteins are frequently expressed at high levels in cancer cells and represent attractive therapeutic targets. We previously reported that the Smac (second mitochondria-derived activator of caspases) mimetic BV6, which antagonizes IAP proteins, sensitizes glioblastoma cells to temozolomide (TMZ)-induced cell death in a nuclear factor-κB (NF-κB)-dependent manner. However, BV6-induced NF-κB target genes responsible for this synergistic interaction have remained elusive. Using whole-genome gene expression profiling, we here identify BV6-stimulated, NF-κB-dependent transcriptional upregulation of interferon-β (IFNβ) and IFN-mediated proapoptotic signaling as critical events that mediate BV6/TMZ-induced apoptosis. Knockdown of IFNβ significantly rescues cells from BV6/TMZ-induced cell death. Similarly, silencing of the corresponding receptor IFNα/β receptor (IFNAR) confers a significant protection against apoptosis, demonstrating that IFNβ and IFN signaling are required for BV6/TMZ-mediated cell death. Moreover, BV6 and TMZ cooperate to transcriptionally upregulate the proapoptotic B-cell lymphoma 2 family proteins Bax (Bcl-2-associated X protein) or Puma (p53-upregulated modulator of apoptosis). Knockdown of Bax or Puma significantly decreases BV6/TMZ-induced apoptosis, showing that both proteins are necessary for apoptosis. By identifying IFNβ as a key mediator of BV6/TMZ-induced apoptosis, our study provides novel insights into the underlying molecular mechanisms of Smac mimetic-mediated chemosensitization with important implications for the development of novel treatment strategies for glioblastoma.
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, Frankfurt 60528, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Marschall
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, Frankfurt 60528, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fulda
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D003606:Dacarbazine / Q000031:analogs & derivatives; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000077204:Temozolomide; D015854:Up-Regulation
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016899:Interferon-beta; D003606:Dacarbazine; D020169:Caspases; D000077204:Temozolomide