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Tytuł pozycji:

To inhibit TrxR1 is to inactivate STAT3–Inhibition of TrxR1 enzymatic function by STAT3 small molecule inhibitors

Tytuł :
To inhibit TrxR1 is to inactivate STAT3–Inhibition of TrxR1 enzymatic function by STAT3 small molecule inhibitors
Autorzy :
Sander Busker
Brent Page
Elias S.J. Arnér
Pokaż więcej
Temat :
Signal transducer and activator of transcription 3
Thioredoxin reductase 1
Small molecule inhibitors
Electrophiles
Selenocysteine
Redox
Medicine (General)
R5-920
Biology (General)
QH301-705.5
Źródło :
Redox Biology, Vol 36, Iss , Pp 101646- (2020)
Wydawca :
Elsevier, 2020.
Rok publikacji :
2020
Kolekcja :
LCC:Medicine (General)
LCC:Biology (General)
Typ dokumentu :
article
Opis pliku :
electronic resource
Język :
English
ISSN :
2213-2317
Relacje :
http://www.sciencedirect.com/science/article/pii/S221323172030851X; https://doaj.org/toc/2213-2317
DOI :
10.1016/j.redox.2020.101646
Dostęp URL :
https://doaj.org/article/59459af66d3f4eccbc09d83825b6ca5e
Numer akcesji :
edsdoj.59459af66d3f4eccbc09d83825b6ca5e
Czasopismo naukowe
The transcription factor STAT3 plays a key role in cancer and immunity, being widely explored as a potential drug target for the development of novel immunomodulatory or anticancer therapeutics. The mechanisms of small molecule-derived inhibition of STAT3 appear, however, to be more complex than initially perceived. Our recent discovery, that some novel STAT3 inhibitors were bona fide inhibitors of the cytosolic selenoprotein oxidoreductase TrxR1 (TXNRD1), led us to explore the effects of a wide array of previously described STAT3 inhibitors on TrxR1 function. We found that 17 out of 23 tested STAT3 small molecule inhibitors indeed inhibited purified TrxR1 at the reported concentrations yielding STAT3 inhibition. All tested compounds were electrophilic as shown by direct reactivities with GSH, and several were found to also be redox cycling substrates of TrxR1. Ten compounds previously shown to inhibit STAT3 were here found to irreversibly inhibit cellular TrxR1 activity (Auranofin, Stattic, 5,15-DPP, Galiellalactone, LLL12, Napabucasin, BP1-102, STA-21, S3I-201 and Degrasyn (WP1130)). Our findings suggest that targeting of TrxR1 may be a common feature for many small molecules that inhibit cellular STAT3 function. It is possible that prevention of STAT3 activation in cells by several small molecules classified as STAT3 inhibitors can be a downstream event following TrxR1 inhibition. Therefore, the relationship between TrxR1 and STAT3 should be considered when studying inhibition of either of these promising drug targets.

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