# The NEDD8 pathway mediated Skp2 degradation in chemoprevention by FKA

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $353,419

## Abstract

Project Summary
 Chemoprevention in unselected populations has been largely unsuccessful; therefore targeting
chemoprevention to high-risk populations by molecular subtyping may represent a promising future strategy.
Flavokawain A (FKA) is a naturally occurring chalcone identified from the kava plant. Epidemiological studies
have suggested that kava consumption may be associated with much lower prostate cancer (PCa) incidence in
the three highest kava-drinking countries (Vanuatu, Fiji, and Western Samoa). We have shown that FKA
selectively inhibits the growth of PCa cell lines and Rb deficient cells compared to normal cells. In addition,
dietary feeding of FKA inhibited the formation of high-grade prostatic intra-epithelial neoplasia lesions and
prostate adenocarcinomas, reduced the tumor burden and completely abolished distant organ metastasis.in
the TRAMP transgenic mouse model without showing any toxicity.
 The mechanism of FKA’s action, in particular the anti-cancer molecular target (s) of FKA, remains
largely unknown. We have therefore carried out extensive preliminary studies. We found that (1) FKA is five
times more effective in inhibiting the growth of PC3 cells with over-expression of Skp2 (the IC50 is about 8 M)
than PC3 cells expressing a vector control; (2) FKA accelerates Skp2 degradation via a proteasome and
ubiquitination dependent pathway; (3) Skp2 degradation by FKA is not dependent on Cdh1 expression but
associated with functional Cullin1; (4) FKA inhibits the conjugation of NEDD8 to Uba3 and Ubc12 in an in vitro
assay and in cell culture; and (5) Given FKA has α, β-unsaturated carbonyl moiety , FKA may react with SH
groups of cysteine in the Uba3 and Ubc12. A focused library of FKA analogs and α, β-unsaturated carbonyl
compounds has therefore been prepared for a structure-activity relationship study. Based on these preliminary
studies, we hypothesize that FKA functions as a novel inhibitor of NEDD8 conjugation and causes Skp2
ubiquitination and degradation; and that FKA exhibits chemopreventive activity by causing the accumulation of
Skp2 substrates (i.e. p27, FOXO1, -TrCP, etc.) leading to cell cycle arrest and apoptosis.
 To test the hypotheses, we will determine: (i) The mechanisms by which FKA inhibits the process of
NEDD8 conjugation; (ii) Whether inhibition of NEDD8 conjugation by FKA is causally associated with Skp2
degradation; (iii) The active concentrations of FKA or FKA metabolites in the mouse prostate and plasma that
can be achieved for effective inhibition of NEDD8 conjugation and for down-regulation Skp2; (vi) Whether
inhibition of the targets (i.e. NEDD8 and Skp2) by FKA at its effective concentrations will prevent or delay
prostate carcinogenesis; (v) Whether more potent Skp2 targeting agents can be identified by studying the
structure-activity relationship of FKA analogs and α, β-unsaturated carbonyl compounds in deNEDDylation and
Skp2 degradation.
 Since pRb and Pten loss are common in PCa and Skp2 has been s...

## Key facts

- **NIH application ID:** 9944457
- **Project number:** 5R01CA193967-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Xiaolin Zi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,419
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944457

## Citation

> US National Institutes of Health, RePORTER application 9944457, The NEDD8 pathway mediated Skp2 degradation in chemoprevention by FKA (5R01CA193967-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9944457. Licensed CC0.

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