Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death
Open Access
- 20 March 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (12), eaax7945
- https://doi.org/10.1126/sciadv.aax7945
Abstract
Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.Funding Information
- Cancerfonden (2015/238, 2018/333)
- Cancerfonden (CAN 2015/698)
- Svenska Sällskapet för Medicinsk Forskning
- Karolinska Institutet
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse (2015.0063)
- Cancerföreningen i Stockholm (174122)
- Vetenskapsrådet (2013-765, 2014-2603, 2017-01872)
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