ArticleOncotarget2015
Flavokawain A induces deNEDDylation and Skp2 degradation leading to inhibition of tumorigenesis and cancer progression in the TRAMP transgenic mouse model.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
39 citing papers in PubMed, 53 citations in OpenAlex.
- Article
- Protein neddylation as a therapeutic target: challenges and opportunities.The Journal of clinical investigation · 2026Review
- Review
- Multi-target therapeutic potential of Flavokawain A in rheumatoid arthritis: A mechanistic and translational perspective.Inflammopharmacology · 2026Review
- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- The Establishment of Prostate-specific, SKP2 Humanized Mice by CRISPR Knock-in Method Reveals Neoplastic Initiation and Microenvironmental Reprogramming.Research square · 2026Article
- The Role of Natural Chalcones and Their Derivatives in Targeting Prostate Cancer: Recent Updates.International journal of molecular sciences · 2025Review
- Deciphering the roles of neddylation modification in hepatocellular carcinoma: Molecular mechanisms and targeted therapeutics.Genes & diseases · 2025Review
- Inhibiting neddylation: A new strategy for tumor therapy.Journal of pharmaceutical analysis · 2025Review
- Pan-cancer analysis unveils the role and mechanisms of neddylation modifications in tumorigenesis.Medical oncology (Northwood, London, England) · 2025Article
- Inhibitors Targeting the F-BOX Proteins.Cell biochemistry and biophysics · 2023Review
- Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions.Journal of hematology & oncology · 2023Review
- Anticancer Potential of Natural Chalcones: In Vitro and In Vivo Evidence.International journal of molecular sciences · 2023Review
- Small-molecule compounds inhibiting S-phase kinase-associated protein 2: A review.Frontiers in pharmacology · 2023Review
- Targeting cullin neddylation for cancer and fibrotic diseases.Theranostics · 2023Review
- Editorial: Phytochemicals in cancer prevention and therapeutics: Current advancement and future perspective.Frontiers in pharmacology · 2023Article
- The Next Frontier: Translational Development of Ubiquitination, SUMOylation, and NEDDylation in Cancer.International journal of molecular sciences · 2022Review
- Chemoprevention of Urothelial Cell Carcinoma Tumorigenesis by Dietary Flavokawain A in UPII-Mutant Ha-ras Transgenic Mice.Pharmaceutics · 2022Article
- Flavokawain A Reduces Tumor-Initiating Properties and Stemness of Prostate Cancer.Frontiers in oncology · 2022Article
- Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors.Cancers · 2021Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
S phase kinase-associated protein 2 (Skp2) has been shown to be required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb) deficient mice. Here we have demonstrated that flavokawain A (FKA), a novel chalcone from the kava plant, selectively inhibited the growth of pRb deficient cell lines and resulted in a proteasome-dependent and ubiquitination-mediated Skp2 degradation. Degradation of Skp2 by FKA was found to be involved in a functional Cullin1, but independent of Cdh1 expression. Further studies have demonstrated that FKA docked into the ATP binding pocket of the precursor cell-expressed developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) complex, inhibited NEDD8 conjugations to both Cullin1 and Ubc12 in PC3 cells and Ubc12 NEDDylation in an in vitro assay. Finally, dietary feeding of the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with FKA inhibited the formation of high-grade prostatic intra-epithelial neoplasia lesions (HG-PIN) and prostate adenocarcinomas, reduced the tumor burden and completely abolished distant organ metastasis. Immunohistochemistry studies revealed that dietary FKA feeding resulted in marked anti-proliferative and apoptotic effects via down-regulation of Skp2 and NEDD8 and up-regulation of p27/Kip1 in the prostate of TRAMP mice. Our findings therefore provide evidence that FKA is a promising NEDDylation inhibitor for targeting Skp2 degradation in prostate cancer prevention and treatment.
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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 OpenQuestion graph.