ArticleCell death & disease2013
Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis.
Article in Cell death & disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- Cell death in glioblastoma and the central nervous system.Cellular oncology (Dordrecht, Netherlands) · 2025Review
- Review
- Article
- SMAC mimetics inhibit human T cell proliferation and fail to augment type 1 cytokine responses.Cellular immunology · 2023Article
- Dual role of ERK2/NF-κB signaling in TRAIL sensitivity.American journal of cancer research · 2022Article
- BH3-mimetics: recent developments in cancer therapy.Journal of experimental & clinical cancer research : CR · 2021Review
- RelB and Neuroinflammation.Cells · 2021Review
- Chrysanthemulide A induces apoptosis through DR5 upregulation via JNK-mediated autophagosome accumulation in human osteosarcoma cells.Journal of cellular physiology · 2019Article
- Smac mimetic suppresses tunicamycin-induced apoptosis via resolution of ER stress.Cell death & disease · 2019Article
- Intracellular apoptotic pathways: a potential target for reducing joint damage in rheumatoid arthritis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2018Review
- Cell death-based treatment of glioblastoma.Cell death & disease · 2018Review
- microRNA-7 upregulates death receptor 5 and primes resistant brain tumors to caspase-mediated apoptosis.Neuro-oncology · 2018Article
- KLF6 depletion promotes NF-κB signaling in glioblastoma.Oncogene · 2017Article
- The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells.Frontiers in immunology · 2017Article
- Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer.Cellular and molecular life sciences : CMLS · 2017Review
- Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers.Oncotarget · 2016Article
- Cooperative TRAIL production mediates IFNα/Smac mimetic-induced cell death in TNFα-resistant solid cancer cells.Oncotarget · 2016Article
- Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells.Oncotarget · 2015Article
- Smac mimetic-induced upregulation of interferon-β sensitizes glioblastoma to temozolomide-induced cell death.Cell death & disease · 2015Article
- Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic.
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