Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-09

AUTHORS

V Marschall, S Fulda

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. More... »

PAGES

e1888

References to SciGraph publications

  • 2013-03. Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells in CELL DEATH & DISEASE
  • 2014-01. Regulation of type I interferon responses in NATURE REVIEWS IMMUNOLOGY
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  • 2013-02. Smac mimetic sensitizes glioblastoma cells to Temozolomide-induced apoptosis in a RIP1- and NF-κB-dependent manner in ONCOGENE
  • 2006-08. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy in ONCOGENE
  • 2010-06. Targeting mitochondria for cancer therapy in NATURE REVIEWS DRUG DISCOVERY
  • 2008-01. DNA damage-induced cell death: lessons from the central nervous system in CELL RESEARCH
  • 2012-02. Targeting IAP proteins for therapeutic intervention in cancer in NATURE REVIEWS DRUG DISCOVERY
  • 2013-11. Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis in CELL DEATH & DISEASE
  • 2014-02. Smac mimetics and innate immune stimuli synergize to promote tumor death in NATURE BIOTECHNOLOGY
  • 2010-10. Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner in CELL DEATH & DIFFERENTIATION
  • 2014-05. Smac mimetic promotes glioblastoma cancer stem-like cell differentiation by activating NF-κB in CELL DEATH & DIFFERENTIATION
  • 2010-04. IRF-1 transcriptionally upregulates PUMA, which mediates the mitochondrial apoptotic pathway in IRF-1-induced apoptosis in cancer cells in CELL DEATH & DIFFERENTIATION
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/cddis.2015.235

    DOI

    http://dx.doi.org/10.1038/cddis.2015.235

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1043760288

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26379193


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