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EBioMedicine. 2019 Feb 5. pii: S2352-3964(19)30042-8. doi: 10.1016/j.ebiom.2019.01.055. [Epub ahead of print]

PI3K inhibitors protect against glucocorticoid-induced skin atrophy.

Author information

1
Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
2
ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA.
3
Institute for Next Generation Healthcare, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: i-budunova@northwestern.edu.

Abstract

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:

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:

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:

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.

KEYWORDS:

FKBP51; Glucocorticoid receptor; PI3K/mTOR/Akt inhibitor; REDD1; Skin atrophy; mTOR

PMID:
30737086
DOI:
10.1016/j.ebiom.2019.01.055
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