Inhibition of integrin binding to ligand arg-gly-asp motif induces AKT-mediated cellular senescence in hepatic stellate cells.
Cell cycle arrest
Focal adhesion kinase
Liver fibrosis
Murine double-minute clone 2
Senescence-associated secretory phenotype
Journal
Molecular and cellular biochemistry
ISSN: 1573-4919
Titre abrégé: Mol Cell Biochem
Pays: Netherlands
ID NLM: 0364456
Informations de publication
Date de publication:
30 Oct 2023
30 Oct 2023
Historique:
received:
10
07
2023
accepted:
15
10
2023
medline:
30
10
2023
pubmed:
30
10
2023
entrez:
30
10
2023
Statut:
aheadofprint
Résumé
Hepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation. This study investigated whether the inhibitory effects of CWHM12 on HSCs affected cellular senescence. The immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on cellular senescence via the disruption of RGD-mediated binding to integrins. CWHM12 induces cell cycle arrest, senescence-associated beta-galactosidase activity, acquisition of senescence-associated secretory phenotype (SASP), and expression of senescence-associated proteins in HSCs. Further experiments revealed that the phosphorylation of AKT and murine double minute 2 (MDM2) was involved in the effects of CWHM12, and the inhibition of AKT phosphorylation reversed these effects of CWHM12 on HSCs. Pharmacological inhibition of RGD-mediated integrin binding induces senescence in activated HSCs.
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
Hepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation. This study investigated whether the inhibitory effects of CWHM12 on HSCs affected cellular senescence.
METHODS
METHODS
The immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on cellular senescence via the disruption of RGD-mediated binding to integrins.
RESULTS
RESULTS
CWHM12 induces cell cycle arrest, senescence-associated beta-galactosidase activity, acquisition of senescence-associated secretory phenotype (SASP), and expression of senescence-associated proteins in HSCs. Further experiments revealed that the phosphorylation of AKT and murine double minute 2 (MDM2) was involved in the effects of CWHM12, and the inhibition of AKT phosphorylation reversed these effects of CWHM12 on HSCs.
CONCLUSIONS
CONCLUSIONS
Pharmacological inhibition of RGD-mediated integrin binding induces senescence in activated HSCs.
Identifiants
pubmed: 37902885
doi: 10.1007/s11010-023-04883-0
pii: 10.1007/s11010-023-04883-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP19K17428
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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