Article ; Online: Galiellalactone is a direct inhibitor of the transcription factor STAT3 in prostate cancer cells.
The Journal of biological chemistry
2014 Volume 289, Issue 23, Page(s) 15969–15978
Abstract: ... This further validates galiellalactone as a promising direct STAT3 inhibitor for treatment of castration ... The transcription factor STAT3 is constitutively active in several malignancies including ... of prostate cancer cells expressing active STAT3 and induces apoptosis of prostate cancer stem cell-like cells ...
| Abstract | 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 phosphorylated STAT3 (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 the 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). Here we 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. |
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| MeSH term(s) | Amino Acid Sequence ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Lactones/pharmacology ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Models, Molecular ; Molecular Sequence Data ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Protein Binding ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/chemistry ; STAT3 Transcription Factor/metabolism |
| Chemical Substances | Lactones ; STAT3 Transcription Factor ; STAT3 protein, human ; galiellalactone |
| Language | English |
| Publishing date | 2014-04-22 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2997-x |
| ISSN | 1083-351X ; 0021-9258 |
| ISSN (online) | 1083-351X |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M114.564252 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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