ArticleCell death & disease2022
PD-L1 induction via the MEK-JNK-AP1 axis by a neddylation inhibitor promotes cancer-associated immunosuppression.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 36 citations in OpenAlex.
- Protein neddylation as a therapeutic target: challenges and opportunities.The Journal of clinical investigation · 2026Review
- Neddylation Targets and Stabilizes NLRP3 to Augment Inflammasome-Mediated Colitis and Mood Disorder.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Scaling perturbations: beyond genome-scale CRISPR screens.bioRxiv : the preprint server for biology · 2026Article
- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- Post-translational modification networks in tumor radiosensitivity: mechanistic insights and therapeutic opportunities.Journal of translational medicine · 2026Review
- The role of neddylation in colorectal cancer and its therapeutic potential.Discover oncology · 2025Review
- IGF-1 regulates cancer cell immune evasion in prostate cancer.Scientific reports · 2025Article
- LIMCH1 inhibits antitumor immunity by upregulating PDL1 in triple-negative breast cancer.Cell communication and signaling : CCS · 2025Article
- Neddylation regulates the development and function of glutamatergic neurons.Communications biology · 2025Article
- Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies.Molecular cancer · 2025Review
- Pan-cancer analysis unveils the role and mechanisms of neddylation modifications in tumorigenesis.Medical oncology (Northwood, London, England) · 2025Article
- DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway.Cellular and molecular life sciences : CMLS · 2024Article
- The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway.Biomolecules · 2024Review
- Regulation of the water channel aquaporin-2 by cullin E3 ubiquitin ligases.American journal of physiology. Renal physiology · 2024Article
- Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways.Experimental hematology & oncology · 2024Review
- Article
- Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review).International journal of oncology · 2024Review
- Scoparone attenuates PD-L1 expression in human breast cancer cells by MKP-3 upregulation.Animal cells and systems · 2024Article
- Design of siRNA Bioconjugates for Efficient Control of Cancer-Associated Membrane Receptors.ACS omega · 2023Article
- Discovery of neddylation E2s inhibitors with therapeutic activity.Oncogenesis · 2023Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
MLN4924 is a first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE), which is currently in several clinical trials for anti-cancer applications. However, MLN4924 also showed some off-target effects with potential to promote the growth of cancer cells which counteracts its anticancer activity. In this study, we found that MLN4924 increases the levels of PD-L1 mRNA and protein in dose- and time-dependent manners. Mechanistic study showed that this MLN4924 effect is largely independent of neddylation inactivation, but is due to activation of both ERK and JNK signals, leading to AP-1 activation, which is blocked by the small molecule inhibitors of MEK and JNK, respectively. Biologically, MLN4924 attenuates T cell killing in a co-culture model due to PD-L1 upregulation, which can be, at least in part, abrogated by either MEK inhibitor or anti-PD-L1 antibody. In an in vivo BALB/c mouse xenograft tumor model, while MLN4924 alone had no effect, combination with either MEK inhibitor or anti-PD-L1 antibody enhanced the suppression of tumor growth. Taken together, our study provides a sound rationale for effective anticancer therapy in combination of anti-PD-L1 antibody or MEK inhibitor with MLN4924 to overcome the side-effect of immunosuppression by MLN4924 via PD-L1 induction.
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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 OpenQuestion graph.