The isothiocyanate sulforaphane inhibits mTOR in an NRF2-independent manner.
HDAC6
NRF2
PI3K-AKT
Sulforaphane
mTOR
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
received:
21
05
2019
revised:
30
07
2019
accepted:
02
08
2019
pubmed:
15
8
2019
medline:
2
6
2021
entrez:
15
8
2019
Statut:
ppublish
Résumé
The isothiocyanate sulforaphane (SFN) has multiple protein targets in mammalian cells, affecting processes of fundamental importance for the maintenance of cellular homeostasis, among which are those regulated by the stress response transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) and the serine/threonine protein kinase mechanistic target of rapamycin (mTOR). Whereas the way by which SFN activates NRF2 is well established, the molecular mechanism(s) of how SFN inhibits mTOR is not understood. The aim of this study was to investigate the mechanism(s) by which SFN inhibits mTOR STUDY DESIGN AND METHODS: We used the human osteosarcoma cell line U2OS and its CRISPR/Cas9-generated NRF2-knockout counterpart to test the requirement for NRF2 and the involvement of mTOR regulators in the SFN-mediated inhibition of mTOR. SFN inhibits mTOR in a concentration- and time-dependent manner, and this inhibition occurs in the presence or in the absence of NRF2. The phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) is a positive regulator of mTOR, and treatment with SFN caused an increase in the phosphorylation of AKT at T308 and S473, two phosphorylation sites associated with AKT activation. Interestingly however, the levels of pS552 β-catenin, an AKT phosphorylation site, were decreased, suggesting that the catalytic activity of AKT was inhibited. In addition, SFN inhibited the activity of the cytoplasmic histone deacetylase 6 (HDAC6), the inhibition of which has been reported to promote the acetylation and decreases the kinase activity of AKT. SFN inhibits HDAC6 and decreases the catalytic activity of AKT, and this partially explains the mechanism by which SFN inhibits mTOR.
Sections du résumé
BACKGROUND
BACKGROUND
The isothiocyanate sulforaphane (SFN) has multiple protein targets in mammalian cells, affecting processes of fundamental importance for the maintenance of cellular homeostasis, among which are those regulated by the stress response transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) and the serine/threonine protein kinase mechanistic target of rapamycin (mTOR). Whereas the way by which SFN activates NRF2 is well established, the molecular mechanism(s) of how SFN inhibits mTOR is not understood.
HYPOTHESIS/PURPOSE
OBJECTIVE
The aim of this study was to investigate the mechanism(s) by which SFN inhibits mTOR STUDY DESIGN AND METHODS: We used the human osteosarcoma cell line U2OS and its CRISPR/Cas9-generated NRF2-knockout counterpart to test the requirement for NRF2 and the involvement of mTOR regulators in the SFN-mediated inhibition of mTOR.
RESULTS
RESULTS
SFN inhibits mTOR in a concentration- and time-dependent manner, and this inhibition occurs in the presence or in the absence of NRF2. The phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) is a positive regulator of mTOR, and treatment with SFN caused an increase in the phosphorylation of AKT at T308 and S473, two phosphorylation sites associated with AKT activation. Interestingly however, the levels of pS552 β-catenin, an AKT phosphorylation site, were decreased, suggesting that the catalytic activity of AKT was inhibited. In addition, SFN inhibited the activity of the cytoplasmic histone deacetylase 6 (HDAC6), the inhibition of which has been reported to promote the acetylation and decreases the kinase activity of AKT.
CONCLUSION
CONCLUSIONS
SFN inhibits HDAC6 and decreases the catalytic activity of AKT, and this partially explains the mechanism by which SFN inhibits mTOR.
Identifiants
pubmed: 31409554
pii: S0944-7113(19)30228-4
doi: 10.1016/j.phymed.2019.153062
pmc: PMC8106549
pii:
doi:
Substances chimiques
Isothiocyanates
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
Sulfoxides
0
MTOR protein, human
EC 2.7.1.1
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
sulforaphane
GA49J4310U
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
153062Subventions
Organisme : Cancer Research UK
ID : 10270
Pays : United Kingdom
Informations de copyright
Copyright © 2019. Published by Elsevier GmbH.
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