PI3K inhibitors protect against glucocorticoid-induced skin atrophy.
Animals
Atrophy
Cell Survival
/ drug effects
Cells, Cultured
Glucocorticoids
/ pharmacology
Humans
Keratinocytes
/ cytology
Mice
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-akt
/ antagonists & inhibitors
Receptors, Glucocorticoid
/ metabolism
Skin
/ drug effects
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Tacrolimus Binding Proteins
/ antagonists & inhibitors
Transcription Factors
/ antagonists & inhibitors
Transcriptome
/ drug effects
Wortmannin
/ pharmacology
FKBP51
Glucocorticoid receptor
PI3K/mTOR/Akt inhibitor
REDD1
Skin atrophy
mTOR
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Mar 2019
Mar 2019
Historique:
received:
29
10
2018
revised:
16
01
2019
accepted:
17
01
2019
pubmed:
10
2
2019
medline:
13
7
2019
entrez:
10
2
2019
Statut:
ppublish
Résumé
Skin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids. Using drug repurposing approach, we screened LINCS library (http://lincsproject.org/LINCS/) to identify repressors of REDD1/FKBP51 expression. Candidate compounds were tested for their ability to inhibit glucocorticoid-induced REDD1/FKBP51 expression in human primary/immortalized keratinocytes and in mouse skin. Reporter gene expression, microarray, and chromatin immunoprecipitation were employed to evaluate effect of these inhibitors on the glucocorticoid receptor (GR) signaling. Bioinformatics analysis unexpectedly identified phosphoinositide-3-kinase (PI3K)/mTOR/Akt inhibitors as a pharmacological class of REDD1/FKBP51 repressors. Selected PI3K/mTOR/Akt inhibitors-Wortmannin (WM), LY294002, AZD8055, and two others indeed blocked REDD1/FKBP51expression in human keratinocytes. PI3K/mTOR/Akt inhibitors also modified global effect of glucocorticoids on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted GR phosphorylation; nuclear translocation; and GR loading on REDD1/FKBP51 gene promoters. Further, topical application of LY294002 together with glucocorticoid fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and skin atrophy but did not alter the anti-inflammatory activity of FA in ear edema test. Our results built a strong foundation for development of safer GR-targeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors. FUND: Work is supported by NIH grants R01GM112945, R01AI125366, and HESI-THRIVE foundation.
Sections du résumé
BACKGROUND
BACKGROUND
Skin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids.
METHODS
METHODS
Using drug repurposing approach, we screened LINCS library (http://lincsproject.org/LINCS/) to identify repressors of REDD1/FKBP51 expression. Candidate compounds were tested for their ability to inhibit glucocorticoid-induced REDD1/FKBP51 expression in human primary/immortalized keratinocytes and in mouse skin. Reporter gene expression, microarray, and chromatin immunoprecipitation were employed to evaluate effect of these inhibitors on the glucocorticoid receptor (GR) signaling.
FINDINGS
RESULTS
Bioinformatics analysis unexpectedly identified phosphoinositide-3-kinase (PI3K)/mTOR/Akt inhibitors as a pharmacological class of REDD1/FKBP51 repressors. Selected PI3K/mTOR/Akt inhibitors-Wortmannin (WM), LY294002, AZD8055, and two others indeed blocked REDD1/FKBP51expression in human keratinocytes. PI3K/mTOR/Akt inhibitors also modified global effect of glucocorticoids on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted GR phosphorylation; nuclear translocation; and GR loading on REDD1/FKBP51 gene promoters. Further, topical application of LY294002 together with glucocorticoid fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and skin atrophy but did not alter the anti-inflammatory activity of FA in ear edema test.
INTERPRETATION
CONCLUSIONS
Our results built a strong foundation for development of safer GR-targeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors. FUND: Work is supported by NIH grants R01GM112945, R01AI125366, and HESI-THRIVE foundation.
Identifiants
pubmed: 30737086
pii: S2352-3964(19)30042-8
doi: 10.1016/j.ebiom.2019.01.055
pmc: PMC6441871
pii:
doi:
Substances chimiques
DDIT4 protein, human
0
Glucocorticoids
0
Phosphoinositide-3 Kinase Inhibitors
0
Protein Kinase Inhibitors
0
Receptors, Glucocorticoid
0
Transcription Factors
0
MTOR protein, human
EC 2.7.1.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Tacrolimus Binding Proteins
EC 5.2.1.-
tacrolimus binding protein 5
EC 5.2.1.8
Wortmannin
XVA4O219QW
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
526-537Subventions
Organisme : NIAMS NIH HHS
ID : P30 AR057216
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI125366
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM112945
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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