Evidence map›Paper›PMID 30885218›Full record

ArticleCell communication and signaling : CCS2019

Flavokawain B targets protein neddylation for enhancing the anti-prostate cancer effect of Bortezomib via Skp2 degradation.

Xuesen Li, Victor Pham, Matthew Tippin, Dongjun Fu, Raymond Rendon, Liankun Song, Edward Uchio, Bang H Hoang, Xiaolin Zi

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell communication and signaling : CCS, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.

0numbers the graph read from it
0cells of the map it votes in
27citing papers in PubMed
1.4field-weighted citation impact, top 19% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

27 citing papers in PubMed, 35 citations in OpenAlex.

  1. Review
  2. Review
  3. Therapeutic Potential of Plant Phenolic Acids Combating Cancer Drug Resistance.Recent advances in food, nutrition & agriculture · 2026
    Review
  4. Review
  5. Frontiers in immunology · 2026
    Article
  6. Review
  7. Review
  8. Review
  9. Inhibiting neddylation: A new strategy for tumor therapy.Journal of pharmaceutical analysis · 2025
    Review
  10. Review
  11. Article
  12. Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024
    Review
  13. A Novel Tri-Hydroxy-Methylated Chalcone Isolated fromInternational journal of molecular sciences · 2023
    Article
  14. Review
  15. Anticancer Potential of Natural Chalcones: In Vitro and In Vivo Evidence.International journal of molecular sciences · 2023
    Review
  16. Review
  17. Flavokawain A is a natural inhibitor of PRMT5 in bladder cancer.Journal of experimental & clinical cancer research : CR · 2022
    Article
  18. Article
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 2 countries.

Xuesen LiDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Victor PhamDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Matthew TippinDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Dongjun FuDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Raymond RendonDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Liankun SongDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Edward UchioDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Bang H HoangDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA.
Xiaolin ZiDepartment of Urology, University of California, Irvine, 101 The City Drive South, Rt.81, Bldg.55, Rm.302, Irvine, Orange, CA, 92868, USA. xzi@uci.edu.ORCID 0000-0002-5312-7158
University of California, Irvine · USChapman University · US

Funding

The NEDD8 pathway mediated Skp2 degradation in chemoprevention by FKAR01CA193967 · NCI · UNIVERSITY OF CALIFORNIA-IRVINE · PI ZI, XIAOLIN · 2016 to 2020
$1.8M
NCI NIH HHS R01 CA193967
6 · The paper itself

Abstract

backgroundFlavokawain B (FKB) has been identified from kava root extracts as a potent apoptosis inducer for inhibiting the growth of various cancer cell lines, including prostate cancer. However, the molecular targets of FKB in prostate cancer cells remain unknown.

methodsAn in vitro NEDD8 Initiation Conjugation Assay was used to evaluate the neddylation inhibitory activity of FKB. Molecular docking and a cellular thermal shift assay were performed to assess the direct interaction between FKB and the NEDD8 activating enzyme (NAE) complex. Protein neddylation, ubiqutination, stability and expression in cells were assessed with immunoprecipitation and Western blotting methods using specific antibodies. Deletion and site specific mutants and siRNAs were used to evaluate deep mechanisms by which FKB induces Skp2 degradation. Cell growth inhibition and apoptosis induction were measured by MTT, ELISA and Western blotting methods.

resultsFKB inhibits NEDD8 conjugations to both Cullin1 and Ubc12 in prostate cancer cell lines and Ubc12 neddylation in an in vitro assay. Molecular docking study and a cellular thermal shift assay reveal that FKB interacts with the regulatory subunit (i.e. APP-BP1) of the NAE. In addition, FKB causes Skp2 degradation in an ubiquitin and proteasome dependent manner. Overexpression of dominant-negative cullin1 (1-452), K720R mutant (the neddylation site) Cullin1 or the F-box deleted Skp2 that losses its binding to the Skp1/Cullin1 complex causes the resistance to FKB-induced Skp2 degradation, whereas siRNA knock-down of Cdh1, a known E3 ligase of Skp2 for targeted degradation, didn't attenuate the effect of FKB on Skp2 degradation. These results suggest that degradation of Skp2 by FKB is involved in a functional Cullin1. Furthermore, proteasome inhibitors Bortezomib and MG132 transcriptionally down-regulate the expression of Skp2, and their combinations with FKB result in enhanced inhibitory effects on the growth of prostate cancer cell lines via synergistic down-regulation of Skp2 and up-regulation of p27/Kip1 and p21/WAF1 protein expression. FKB also selectively inhibits the growth of RB deficient cells with high expression of Skp2.

conclusionThese findings provide a rationale for further investigating combination of FKB and Bortezomib for treatment of RB deficient, castration-resistant prostate cancer.

Indexed as

Antigens, CDAntineoplastic AgentsApoptosisBortezomibCadherinsCell ProliferationCullin ProteinsFlavonoidsHumansLeupeptinsMaleNEDD8 ProteinPC-3 CellsProstatic Neoplasms, Castration-ResistantS-Phase Kinase-Associated ProteinsUbiquitin-Activating EnzymesAntigens, CDAntineoplastic Agentsbenzyloxycarbonylleucyl-leucyl-leucine aldehydeBortezomibCACUL1 protein, humanCadherinsCDH1 protein, humanCullin Proteinsflavokawain BFlavonoidsLeupeptinsNAE protein, humanNEDD8 ProteinNEDD8 protein, humanSKP1 protein, humanSKP2 protein, humanS-Phase Kinase-Associated ProteinsUBE2M protein, humanUbiquitin-Activating EnzymesUbiquitin-Conjugating EnzymesAnd prostate cancerChalconeNeddylationSkp2

Identifiers

PMID30885218
PMCPMC6423783
OpenAlexW2943760001

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.