The JAK2/STAT3 pathway inhibitor, AG490, suppresses the abnormal behavior of keloid fibroblasts in vitro.
Int J Mol Med
; 46(1): 191-200, 2020 Jul.
Article
in En
| MEDLINE
| ID: mdl-32377718
ABSTRACT
AG490 is a selective inhibitor of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The present study examined its effects on the abnormal behavior of human keloid fibroblasts (HKFs) and evaluated its potential use in the treatment of keloids. Human normal fibroblasts (HNFs) and HKFs were treated with increasing concentrations of AG490. The proliferation of HNFs and HKFs was inhibited by AG490 in both a time and concentrationdependent manner by increasing apoptosis and inducing G1 cell cycle arrest. The downregulation of cyclin D1 and connective tissue growth factor (CTGF) expression was associated with a decrease in STAT3 expression in response to AG490. The effects of AG490 on TGFßstimulated fibroblasts, including HNFs, HKFs and hypertrophic scar fibroblasts (HSFs) were also evaluated. The TGFß1stimulated excessive proliferation and CTGF production were markedly inhibited by the application of AG490 in the HNFs, HSFs and HKFs. In addition, the STAT3specific decoy oligodeoxynucleotides (SODNs) were transfected into HKFs. The invasive ability of the SODNtransfected HKFs was determined and the expression of extracellular matrix components was quantified. Similarly, SODNs blocked the constitutive activation of STAT3. SODNs inhibited the invasion and progression of HKFs, possibly via the upregulation of the expression of tissue inhibitor of metalloproteinase2 (TIMP2), and the downregulation of the expression of matrix metalloproteinase2 (MMP2) and vascular endothelial growth factor (VEGF). On the whole, the findings of the present study demonstrate that STAT3specific elimination, such as the application of AG490 and decoy ODNs, may serve as promising therapeutic strategies for the treatment of keloids.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tyrphostins
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STAT3 Transcription Factor
/
Janus Kinase 2
/
Fibroblasts
Limits:
Humans
Language:
En
Journal:
Int J Mol Med
Journal subject:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Year:
2020
Type:
Article