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.
Highlights
Evasion of programmed cell death is one of the hallmarks of human cancers[3] and promotes tumorigenesis as well as treatment resistance.[4]
We assessed cell death upon treatment with the chemotherapeutic agent TMZ and the second mitochondria-derived activator of caspases (Smac) mimetic BV6 using the glioblastoma cell lines A172 and T98G to confirm that Smac mimetic enhances TMZ-induced apoptosis, as we reported previously.[12]
We previously reported nuclear factor-κB (NF-κB)-dependent sensitization of glioblastoma cells to TMZ-induced apoptosis by the Smac mimetic BV6 as a novel approach to enhance the efficacy of conventional chemotherapy in glioblastoma.[12]
Summary
Evasion of programmed cell death is one of the hallmarks of human cancers[3] and promotes tumorigenesis as well as treatment resistance.[4] Apoptosis is a common form of programmed cell death that can be engaged via the intrinsic (mitochondrial) or extrinsic (death receptor) pathway.[5] Activation of the intrinsic pathway is controlled by pro- and antiapoptotic B-cell lymphoma 2 (Bcl-2) family protein, including Bcl-2 family proteins such as p53-upregulated modulator of apoptosis (Puma) or Bcl-2-associated X protein (Bax). Following engagement of the mitochondrial pathway, mitochondrial intermembrane space proteins are released into the cytosol, including second mitochondria-derived activator of caspases (Smac).[6] Smac binds to and neutralizes Inhibitor of Apoptosis (IAP) proteins, a family of antiapoptotic proteins, thereby promoting activation of caspases and apoptosis.[7]. We aimed at discovering novel NF-κB-dependent factors that are required for the cooperative anticancer activity of BV6 and TMZ, the prototypic chemotherapeutic agent used for the treatment of glioblastoma
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