Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death
| Autor: | Iryna Kolosenko, Jianping Liu, Lars-Olof Johansson, Wang Qian, B. Espinosa, Sander Busker, K. Pokrovskaja Tamm, Elias S.J. Arnér, Sanaz Attarha, Brent D. G. Page, Martin Haraldsson, Dan Grandér, Markus Dagnell |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
STAT3 Transcription Factor
Transcriptional Activation Drug Thioredoxin Reductase 1 NF-E2-Related Factor 2 media_common.quotation_subject Cell- och molekylärbiologi Antineoplastic Agents Biochemistry 03 medical and health sciences 0302 clinical medicine Genes Reporter Transcription (biology) Cell Line Tumor Humans Luciferase Enzyme Inhibitors STAT3 Gene Research Articles Cancer 030304 developmental biology media_common Regulation of gene expression 0303 health sciences Multidisciplinary Cell Death Dose-Response Relationship Drug biology Chemistry SciAdv r-articles Gene Expression Regulation Neoplastic Oxidative Stress Cell culture 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Oxidation-Reduction Cell and Molecular Biology Research Article |
| Zdroj: | Science Advances |
| Popis: | Redox regulation of STAT3 is targeted by direct inhibition of TrxR1, illuminating a promising link for therapeutic development. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|