ArticleCancers2020
Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma.
Article in Cancers, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 38 citations in OpenAlex.
- NRF1 is upregulated by docosahexaenoic acid to ameliorate MASH through the inhibition of ER stress.Cell death & disease · 2026Article
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- Article
- HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer.British journal of cancer · 2024Article
- The human retroviral-like aspartic protease 1 (ASPRV1): From in vitro studies to clinical correlations.The Journal of biological chemistry · 2024Review
- Mutations in nucleotide metabolism genes bypass proteasome defects in png-1/NGLY1-deficient Caenorhabditis elegans.PLoS biology · 2024Article
- The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducing p62 and GABARAPL1 after proteasome inhibition to maintain proteostasis.Scientific reports · 2023Article
- α-Tocotrienol and Redox-Silent Analogs of Vitamin E Enhances Bortezomib Sensitivity in Solid Cancer Cells through Modulation of NFE2L1.International journal of molecular sciences · 2023Article
- Drug Resistance and Novel Therapies in Cancers in 2020.Cancers · 2023Article
- Viral proteases as therapeutic targets.Molecular aspects of medicine · 2022Review
- Article
- Aspartyl Protease Inhibitors as Anti-Filarial Drugs.Pathogens (Basel, Switzerland) · 2022Article
- The aspartyl protease DDI2 drives adaptation to proteasome inhibition in multiple myeloma.Cell death & disease · 2022Article
- Mammalian Ddi2 is a shuttling factor containing a retroviral protease domain that influences binding of ubiquitylated proteins and proteasomal degradation.The Journal of biological chemistry · 2022Article
- Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival.Blood advances · 2022Article
- Structural and functional insights into the DNA damage-inducible protein 1 (Ddi1) from protozoa.Current research in structural biology · 2022Article
- Treatment with HIV-Protease Inhibitor Nelfinavir Identifies Membrane Lipid Composition and Fluidity as a Therapeutic Target in Advanced Multiple Myeloma.Cancer research · 2021Article
- Review
- Roles of NRF3 in the Hallmarks of Cancer: Proteasomal Inactivation of Tumor Suppressors.Cancers · 2020Review
- Targeting NF-κB Signaling for Multiple Myeloma.Cancers · 2020Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir's effectiveness in the treatment of multiple myeloma.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.