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Galiellalactone is a Direct Inhibitor of STAT3 in Prostate Cancer Cells.

Don-Doncow, Nicholas LU ; Escobar Gabriel, Zilma LU ; Johansson, Martin H LU ; Kjellström, Sven LU ; Garcia, Victor; Munoz, Eduardo; Sterner, Olov LU ; Bjartell, Anders LU and Hellsten, Rebecka LU (2014) In Journal of Biological Chemistry 289(23). p.15969-15978
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 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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
289
issue
23
pages
15969 - 15978
publisher
ASBMB
external identifiers
  • wos:000337965700008
  • pmid:24755219
  • scopus:84902169125
ISSN
1083-351X
DOI
10.1074/jbc.M114.564252
language
English
LU publication?
yes
id
3f857e17-4223-42ec-95a6-2a42a9d6d04c (old id 4429641)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24755219?dopt=Abstract
date added to LUP
2014-05-04 15:35:51
date last changed
2017-10-01 03:08:57
@article{3f857e17-4223-42ec-95a6-2a42a9d6d04c,
  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 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.},
  author       = {Don-Doncow, Nicholas and Escobar Gabriel, Zilma and Johansson, Martin H and Kjellström, Sven and Garcia, Victor and Munoz, Eduardo and Sterner, Olov and Bjartell, Anders and Hellsten, Rebecka},
  issn         = {1083-351X},
  language     = {eng},
  number       = {23},
  pages        = {15969--15978},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Galiellalactone is a Direct Inhibitor of STAT3 in Prostate Cancer Cells.},
  url          = {http://dx.doi.org/10.1074/jbc.M114.564252},
  volume       = {289},
  year         = {2014},
}