Urolithin A gains in antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells.
Journal
Carcinogenesis
ISSN: 1460-2180
Titre abrégé: Carcinogenesis
Pays: England
ID NLM: 8008055
Informations de publication
Date de publication:
12 03 2019
12 03 2019
Historique:
received:
04
07
2018
revised:
16
10
2018
accepted:
07
11
2018
pubmed:
13
11
2018
medline:
8
11
2019
entrez:
13
11
2018
Statut:
ppublish
Résumé
Polyphenols have shown promising bioactivity in experimental in vitro and in vivo models for cancer chemoprevention. However, consumed orally, they are often transformed by gut microbes into new active principles with so far incompletely deciphered molecular mechanisms. Here, enterolacton, S-equol and urolithin A as representatives of metabolites of lignans, isoflavones and ellagitannins, respectively, were examined for their impact on HCT116 colon cancer cell growth, cooperativity with oxaliplatin and p53 dependency in vitro. Whereas enterolacton and S-equol (≤60 µM) did not elicit growth inhibition or positive cooperativity with oxaliplatin, urolithin A showed an IC50 value of 19 µM (72 h) and synergism with oxaliplatin. Urolithin A induced p53 stabilization and p53 target gene expression, and absence of p53 significantly dampened the antiproliferative effect of urolithin A (IC50(p53-/-) = 38 µM). P53 was dispensable for the G2/M arrest in HCT116 cells but required for induction of a senescence-like phenotype upon long-term exposure and for the observed synergism with oxaliplatin. Moreover, extracellular flux analyses and knockdown approaches uncovered a reduced glycolytic potential via the p53/TIGAR axis which was linked to the higher susceptibility of wildtype cells to urolithin A. Overall, the p53 status turned out to be an important determinant for the potential benefit of dietary ellagitannins in cancer chemoprevention or use in adjuvant therapy.
Identifiants
pubmed: 30418550
pii: 5173445
doi: 10.1093/carcin/bgy158
pmc: PMC6412115
mid: EMS82230
doi:
Substances chimiques
Apoptosis Regulatory Proteins
0
Coumarins
0
Tumor Suppressor Protein p53
0
Oxaliplatin
04ZR38536J
3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
1143-70-0
Phosphoric Monoester Hydrolases
EC 3.1.3.2
TIGAR protein, human
EC 3.1.3.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
93-101Subventions
Organisme : Austrian Science Fund FWF
ID : P 29392
Pays : Austria
Informations de copyright
© The Author(s) 2018. Published by Oxford University Press.
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