Galiellalactone is a Direct Inhibitor of STAT3 in Prostate Cancer Cells.
Author
Summary, in English
The transcription factor STAT3 is constitutively active in several malignancies including castration-resistant prostate cancer and has been identified as a promising therapeutic target. The fungal metabolite galiellalactone, a STAT3 signaling inhibitor, inhibits the growth, both in vitro and in vivo, of prostate cancer cells expressing active STAT3 and induces apoptosis of prostate cancer stem cell-like cells expressing pSTAT3. However, the molecular mechanism of this STAT3 inhibiting effect by galiellalactone has not been clarified. A biotinylated analogue of galiellalactone (GL-biot) was synthesized to be used for identification of galiellalactone target proteins. By adding streptavidin-sepharose beads to GL-biot treated DU145 cell lysates, STAT3 was isolated and identified as a target protein. Confocal microscopy revealed GL-biot in both the cytoplasm and nucleus of DU145 cells treated with GL-biot, appearing to co-localize with STAT3 in the nucleus. Galiellalactone inhibited STAT3 binding to DNA in DU145 cell lysates without affecting phosphorylation status of STAT3. Mass spectrometry analysis of recombinant STAT3 protein pretreated with galiellalactone revealed three modified cysteines (cys-367, cys-468 and cys-542). We here demonstrate with chemical and molecular pharmacological methods that galiellalactone is a cysteine reactive inhibitor that covalently binds to one or more cysteines in STAT3 and that this leads to inhibition of STAT3 binding to DNA and thus blocks STAT3 signaling without affecting phosphorylation. This further validates galiellalactone as a promising direct STAT3 inhibitor for treatment of castration-resistant prostate cancer.
Department/s
- Urological cancer, Malmö
- Centre for Analysis and Synthesis
- Medical Protein Science
- Biochemistry and Structural Biology
- Faculty of Science
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- EpiHealth: Epidemiology for Health
Publishing year
2014
Language
English
Pages
15969-15978
Publication/Series
Journal of Biological Chemistry
Volume
289
Issue
23
Links
Document type
Journal article
Publisher
American Society for Biochemistry and Molecular Biology
Topic
- Cell and Molecular Biology
Status
Published
Research group
- Urological cancer, Malmö
- Medical Protein Science
ISBN/ISSN/Other
- ISSN: 1083-351X