Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death

Busker, Sander; Wang, Qian; Haraldsson, Martin; Espinosa, Belén; Johansson, Linda; Attarha, Sanaz; Kolosenko, Iryna; Liu, Jianping; Dagnell, Markus; Grandér, Dan; Arnér, Elias S.J.; Tamm, Katja Pokrovskaja; Page, Brent D. G.

doi:10.1126/sciadv.aax7945

Cited by 56 publications

(57 citation statements)

References 43 publications

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“…Redox regulation of STAT3 also occurs via oxidation and reduction of exposed Cys residues, through a redox relay involving peroxiredoxin-2 (Prx2) and thioredoxin-1 (Trx1) [ 83 , 84 ]. Following induction of oxidative stress by H 2 O 2 , Prx2 rapidly oxidizes STAT3 inducing the formation of unphosphorylated STAT3 dimer transcriptionally inactive.…”

Section: Redox Regulation Of Stat1 and Stat3 Signaling Cascadementioning

confidence: 99%

Redox Regulation of STAT1 and STAT3 Signaling

Butturini

Prati

Mariotto

2020

IJMS

112

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STAT1 and STAT3 are nuclear transcription factors that regulate genes involved in cell cycle, cell survival and immune response. The cross-talk between these signaling pathways determines how cells integrate the environmental signals received ultimately translating them in transcriptional regulation of specific sets of genes. Despite being activated downstream of common cytokine and growth factors, STAT1 and STAT3 play essentially antagonistic roles and the disruption of their balance directs cells from survival to apoptotic cell death or from inflammatory to anti-inflammatory responses. Different mechanisms are proposed to explain this yin-yang relationship. Considering the redox aspect of STATs proteins, this review attempts to summarize the current knowledge of redox regulation of STAT1 and STAT3 signaling focusing the attention on the post-translational modifications that affect their activity.

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Section: Redox Regulation Of Stat1 and Stat3 Signaling Cascadementioning

confidence: 99%

Redox Regulation of STAT1 and STAT3 Signaling

Butturini

Prati

Mariotto

2020

IJMS

112

View full text Add to dashboard Cite

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“…It has become clear that the biochemical and cellular effects of these inhibitors might also be caused by other mechanisms than direct binding to STAT3 in cells [ 15 ]. Recently, we found that several novel STAT3 inhibitors exerted their effects via covalent inhibition of Thioredoxin Reductase 1 (TrxR1, TXNRD1), rather than STAT3.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we found that several novel STAT3 inhibitors exerted their effects via covalent inhibition of Thioredoxin Reductase 1 (TrxR1, TXNRD1), rather than STAT3. In a cellular setting, inhibition of TrxR1 readily leads to oxidation of STAT3 cysteine residues, thereby impairing the transcriptional function of STAT3 [ 15 , 16 ]. Oxidation of STAT3 cysteine residues leads to the formation of inactive STAT3 multimeric or dimeric covalently bound disulfide-linked complexes [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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

2020

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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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“…Phosphorylation of tyrosine 705 residue induced by epidermal growth factor (EGF) or interleukins can activate STAT-3 in cells [4]. STAT-3 can facilitate cancer progression and metastasis by being constitutively active via various signaling as previously described [5,6]. Abundant evidences have indicated that STAT-3 may be a promising molecular target for cancer treatment.…”

Section: Backgroudmentioning

confidence: 94%

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

Hong

Lee

Clayton

et al. 2020

Preprint

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Background Signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signalling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment. Methods In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in patient-derived xenograft mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination and immunofluorescence were utilized to evaluate the regulatory signalling pathway. Results Our research have demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may attribute to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, we also demonstrated the therapeutic effects of genipin in patient-derived HCC xenograft mice model.Conclusion In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with SH2-STAT-3 domain and suppressing the activity of STAT-3. In future study, further research are expected for exploring the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.

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Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death

Cited by 56 publications

References 43 publications

Redox Regulation of STAT1 and STAT3 Signaling

Redox Regulation of STAT1 and STAT3 Signaling

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

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

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