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Irreversible TrxR1 inhibitors block STAT3 activity and induce cancer cell death

S Busker1, W Qian2, M Haraldsson3

  • 1Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Science Advances
|March 29, 2020
PubMed

Insights

New cancer therapeutics targeting STAT3 may work indirectly. Researchers found compounds blocking STAT3 signaling actually inhibit TrxR1, leading to STAT3 oxidation and reduced cancer cell transcription.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is crucial in cancer development and progression.
  • STAT3 inhibitors are being developed as cancer therapeutics, but their mechanisms are complex.
  • STAT3's role in cancer necessitates a deeper understanding of its regulation.

Purpose of the Study:

  • To identify and optimize compounds that inhibit STAT3-dependent transcription.
  • To elucidate the underlying mechanisms of action for novel STAT3 inhibitors.
  • To explore the relationship between STAT3 inhibition and other cellular targets.

Main Methods:

  • Compound screening for inhibition of STAT3-dependent luciferase expression.
  • Biochemical assays to determine direct binding targets of lead compounds.
  • Analysis of protein oxidation states (STAT3, Prx2) following target inhibition.
  • Testing established STAT3 and TrxR1 inhibitors for cross-activity.

Main Results:

  • Optimized compounds potently blocked STAT3-dependent transcription but did not bind STAT3.
  • Lead compounds inhibited thioredoxin reductase 1 (TrxR1).
  • TrxR1 inhibition led to STAT3 and Prx2 oxidation, blocking STAT3 transcription.
  • Both previously identified STAT3 and TrxR1 inhibitors showed cross-reactivity.

Conclusions:

  • STAT3 signaling can be effectively blocked by inhibiting TrxR1.
  • This reveals a novel mechanism involving TrxR1-mediated STAT3 oxidation.
  • Understanding these complex redox regulations offers new therapeutic strategies for cancer.

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