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Smac mimetic-induced upregulation of interferon-? 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-?B (NF-?B)-dependent manner. However, BV6-induced NF-?B target genes responsible for this synergistic interaction have remained elusive. Using whole-genome gene expression profiling, we here identify BV6-stimulated, NF-?B-dependent transcriptional upregulation of interferon-? (IFN?) and IFN-mediated proapoptotic signaling as critical events that mediate BV6/TMZ-induced apoptosis. Knockdown of IFN? significantly rescues cells from BV6/TMZ-induced cell death. Similarly, silencing of the corresponding receptor IFN?/? receptor (IFNAR) confers a significant protection against apoptosis, demonstrating that IFN? 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 IFN? 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.

SUBMITTER: Marschall V

PROVIDER: S-EPMC4650438 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death.

Marschall V V Fulda S S

Cell death & disease 20150917

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 ...[more]

PMID: 26379193

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Project description:Redox mechanisms play an important role in the control of various signaling pathways. Here, we report that Second mitochondrial activator of caspases (Smac) mimetic-induced cell death is regulated by redox signaling. We show that RSL3, a glutathione (GSH) peroxidase (GPX) 4 inhibitor, or Erastin, an inhibitor of the cystine/glutamate antiporter, cooperate with the Smac mimetic BV6 to induce reactive oxygen species (ROS)-dependent cell death in acute lymphoblastic leukemia (ALL) cells. Addition of the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to rescue ROS-induced cell death, demonstrating that RSL3/BV6- or Erastin/BV6-induced cell death occurs in a caspase-independent manner. Interestingly, the iron chelator Deferoxamine (DFO) significantly inhibits RSL3/BV6-induced cell death, whereas it is unable to rescue cell death by Erastin/BV6, showing that RSL3/BV6-, but not Erastin/BV6-mediated cell death depends on iron. ROS production is required for both RSL3/BV6- and Erastin/BV6-induced cell death, since the ROS scavenger α-tocopherol (α-Toc) rescues RSL3/BV6- and Erastin/BV6-induced cell death. By comparison, genetic or pharmacological inhibition of lipid peroxidation by GPX4 overexpression or ferrostatin (Fer)-1 significantly decreases RSL3/BV6-, but not Erastin/BV6-induced cell death, despite inhibition of lipid peroxidation upon exposure to RSL3/BV6 or Erastin/BV6. Of note, inhibition of lipid peroxidation by Fer-1 protects from RSL3/BV6-, but not from Erastin/BV6-stimulated ROS production, indicating that other forms of ROS besides lipophilic ROS occur during Erastin/BV6-induced cell death. Taken together, RSL3/BV6 and Erastin/BV6 differentially regulate redox signaling and cell death in ALL cells. While RSL3/BV6 cotreatment induces ferroptotic cell death, Erastin/BV6 stimulates oxidative cell death independently of iron. These findings have important implications for the therapeutic targeting of redox signaling to enhance Smac mimetic-induced cell death in ALL.

Project description:Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNF? as mediators of IFN?/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFN? to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFN?/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFN?/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNF? signaling by the TNF? scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFN?/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFN?/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNF? and TRAIL signaling, mRNA and protein expression is increased by IFN?/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNF? even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNF? while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNF? determines the dependency on either death receptor ligand for IFN?/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFN?/Smac mimetic combination treatment is an effective strategy to induce cell death in TNF?- or TRAIL-responsive cancers.

Dataset Information

Smac mimetic-induced upregulation of interferon-? sensitizes glioblastoma to temozolomide-induced cell death.

Publications

Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death.

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