ArticleBlood advances2019
Targeting ubiquitin-activating enzyme induces ER stress-mediated apoptosis in B-cell lymphoma cells.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Unveiling the dark side of glucose-regulated protein 78 (GRP78) in cancers and other human pathology: a systematic review.Molecular medicine (Cambridge, Mass.) · 2023Pooled it
- Multifunctional nanotherapeutics for targeted modulation of endoplasmic reticulum stress to potentiate cancer therapy.Asian journal of pharmaceutical sciences · 2026Review
- Multimodal graphene oxide nanoplatform integrating proteasome inhibition and phototherapy for synergistic oral cancer treatment.Scientific reports · 2026Article
- UBA1 promotes cardiac hypertrophy by suppressing autophagy via targeting ATG5 for ubiquitination.Cell communication and signaling : CCS · 2026Article
- UBA1 as a proteostasis-innate immunity checkpoint: lessons from vexas syndrome and therapeutic implications.Frontiers in immunology · 2026Review
- SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms.Leukemia · 2025Article
- Vitreous Humor Proteomic Profile in Patients With Vitreoretinal Lymphoma.Investigative ophthalmology & visual science · 2023Article
- Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.Neuro-oncology · 2023Article
- Progress in Anticancer Drug Development Targeting Ubiquitination-Related Factors.International journal of molecular sciences · 2022Review
- Article
- Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma.Cell death & disease · 2022Article
- Review
- Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling.International journal of molecular sciences · 2021Review
- GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death.Cell death & disease · 2021Article
- Dynamics of replication origin over-activation.Nature communications · 2021Article
- SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243.Cancer research · 2021Article
- Chidamide induces apoptosis in DLBCL cells by suppressing the HDACs/STAT3/Bcl‑2 pathway.Molecular medicine reports · 2021Article
- A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity.JCI insight · 2021Article
- Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC.Molecular oncology · 2020Article
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alterations in the ubiquitin proteasome system (UPS) leave malignant cells in heightened cellular stress, making them susceptible to proteasome inhibition. However, given the limited efficacy of proteasome inhibitors in non-Hodgkin lymphoma (NHL), novel approaches to target the UPS are needed. Here, we show that TAK-243, the first small-molecule inhibitor of the ubiquitin activating enzyme (UAE) to enter clinical development, disrupts all ubiquitin signaling and global protein ubiquitination in diffuse large B-cell lymphoma (DLBCL) cells, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Activation of the ER stress response protein kinase R (PKR)-like ER kinase and phosphorylation of eukaryotic translation initiator factor 2α led to upregulation of the proapoptotic molecule C/EBP homologous protein and cell death across a panel of DLBCL cell lines independent of cell of origin. Concurrently, targeting UAE led to accumulation of Cdt1, a replication licensing factor, leading to DNA rereplication, checkpoint activation, and cell cycle arrest. MYC oncoprotein sensitized DLBCL cells to UAE inhibition; engineered expression of MYC enhanced while genetic MYC knockdown protected from TAK-243-induced apoptosis. UAE inhibition demonstrated enhanced ER stress and UPR and increased potency compared with bortezomib in DLBCL cell lines. In vivo treatment with TAK-243 restricted the growth of xenografted DLBCL tumors, accompanied by reduced cell proliferation and apoptosis. Finally, primary patient-derived DLBCL cells, including those expressing aberrant MYC, demonstrated susceptibility to UAE inhibition. In sum, targeting UAE may hold promise as a novel therapeutic approach in NHL.
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