ArticleCell death & disease2014
Discrepant NOXA (PMAIP1) transcript and NOXA protein levels: a potential Achilles' heel in mantle cell lymphoma.
Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 59 citations in OpenAlex.
- Article
- Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.Blood advances · 2025Article
- Biomarker Signatures in Time-Course Progression of Neuropathic Pain at Spinal Cord Level Based on Bioinformatics and Machine Learning Analysis.Biomolecules · 2025Article
- Targeting the WSB2-NOXA axis in cancer cells for enhanced sensitivity to BCL-2 family protein inhibitors.eLife · 2025Article
- Metabolic Reprogramming and Potential Therapeutic Targets in Lymphoma.International journal of molecular sciences · 2023Review
- SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic target in multiple myeloma.Molecular oncology · 2023Article
- Article
- The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force.Nature communications · 2022Article
- Article
- Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?Cell death and differentiation · 2022Review
- NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in aClinical cancer research : an official journal of the American Association for Cancer Research · 2021Article
- Advances in Cancer Treatment by Targeting the Neddylation Pathway.Frontiers in cell and developmental biology · 2021Review
- Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci.Human molecular genetics · 2020Article
- CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage.Cell death & disease · 2020Article
- Dysregulated metabolic pathways in age-related macular degeneration.Scientific reports · 2020Article
- Potent efficacy of MCL-1 inhibitor-based therapies in preclinical models of mantle cell lymphoma.Oncogene · 2020Article
- Silencing lncRNA LOC101928963 Inhibits Proliferation and Promotes Apoptosis in Spinal Cord Glioma Cells by Binding to PMAIP1.Molecular therapy. Nucleic acids · 2019Article
- SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway.Journal of experimental & clinical cancer research : CR · 2019Article
- Phenotypic miRNA Screen Identifies miR-26b to Promote the Growth and Survival of Endothelial Cells.Molecular therapy. Nucleic acids · 2018Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with transient response to conventional chemotherapy. We here investigated the role of the Bcl-2 homology domain 3-only protein NOXA for life-death decision in MCL. Surprisingly, NOXA (PMAIP1) mRNA and NOXA protein levels were extremely discrepant in MCL cells: NOXA mRNA was found to be highly expressed whereas NOXA protein levels were low. Chronic active B-cell receptor signaling and to a minor degree cyclin D1 overexpression contributed to high NOXA mRNA expression levels in MCL cells. The phoshatidyl-inositol-3 kinase/AKT/mammalian target of rapamycin pathway was identified as the major downstream signaling pathway involved in the maintenance of NOXA gene expression. Interestingly, MCL cells adapt to this constitutive pro-apoptotic signal by extensive ubiquitination and rapid proteasomal degradation of NOXA protein (T½∼15-30 min). In addition to the proteasome inhibitor Bortezomib, we identified the neddylation inhibitor MLN4924 and the fatty acid synthase inhibitor Orlistat as potent inducers of NOXA protein expression leading to apoptosis in MCL. All inhibitors targeted NOXA protein turnover. In contrast to Bortezomib, MLN4924 and Orlistat interfered with the ubiquitination process of NOXA protein thereby offering new strategies to kill Bortezomib-resistant MCL cells. Our data, therefore, highlight a critical role of NOXA in the balance between life and death in MCL. The discrepancy between NOXA transcript and protein levels is essential for sensitivity of MCL to ubiquitin-proteasome system inhibitors and could therefore provide a druggable Achilles' heel of MCL cells.
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