The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway.
Signal transducer and activator of transcription STAT5 and its upstream activating kinase JAK2 are essential mediators of cytokine signaling. Their activity is normally tightly regulated and transient. However, constitutive activation of STAT5 is found in numerous cancers and a driving force for mal...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0090275&type=printable |
| _version_ | 1826799138093662208 |
|---|---|
| author | Sophia Pinz Samy Unser Susanne Brueggemann Elisabeth Besl Nafisah Al-Rifai Hermina Petkes Sabine Amslinger Anne Rascle |
| author_facet | Sophia Pinz Samy Unser Susanne Brueggemann Elisabeth Besl Nafisah Al-Rifai Hermina Petkes Sabine Amslinger Anne Rascle |
| author_sort | Sophia Pinz |
| collection | DOAJ |
| description | Signal transducer and activator of transcription STAT5 and its upstream activating kinase JAK2 are essential mediators of cytokine signaling. Their activity is normally tightly regulated and transient. However, constitutive activation of STAT5 is found in numerous cancers and a driving force for malignant transformation. We describe here the identification of the synthetic chalcone α-Br-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) as a novel JAK/STAT inhibitor. Using the non-transformed IL-3-dependent B cell line Ba/F3 and its oncogenic derivative Ba/F3-1*6 expressing constitutively activated STAT5, we show that α-Br-TMC targets the JAK/STAT pathway at multiple levels, inhibiting both JAK2 and STAT5 phosphorylation. Moreover, α-Br-TMC alters the mobility of STAT5A/B proteins in SDS-PAGE, indicating a change in their post-translational modification state. These alterations correlate with a decreased association of STAT5 and RNA polymerase II with STAT5 target genes in chromatin immunoprecipitation assays. Interestingly, expression of STAT5 target genes such as Cis and c-Myc was differentially regulated by α-Br-TMC in normal and cancer cells. While both genes were inhibited in IL-3-stimulated Ba/F3 cells, expression of the oncogene c-Myc was down-regulated and that of the tumor suppressor gene Cis was up-regulated in transformed Ba/F3-1*6 cells. The synthetic chalcone α-Br-TMC might therefore represent a promising novel anticancer agent for therapeutic intervention in STAT5-associated malignancies. |
| first_indexed | 2024-12-19T19:24:35Z |
| format | Article |
| id | doaj.art-50a618ceab844bf48a2edab3317b3c75 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-03-17T00:30:19Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-50a618ceab844bf48a2edab3317b3c752025-02-21T05:36:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e9027510.1371/journal.pone.0090275The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway.Sophia PinzSamy UnserSusanne BrueggemannElisabeth BeslNafisah Al-RifaiHermina PetkesSabine AmslingerAnne RascleSignal transducer and activator of transcription STAT5 and its upstream activating kinase JAK2 are essential mediators of cytokine signaling. Their activity is normally tightly regulated and transient. However, constitutive activation of STAT5 is found in numerous cancers and a driving force for malignant transformation. We describe here the identification of the synthetic chalcone α-Br-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) as a novel JAK/STAT inhibitor. Using the non-transformed IL-3-dependent B cell line Ba/F3 and its oncogenic derivative Ba/F3-1*6 expressing constitutively activated STAT5, we show that α-Br-TMC targets the JAK/STAT pathway at multiple levels, inhibiting both JAK2 and STAT5 phosphorylation. Moreover, α-Br-TMC alters the mobility of STAT5A/B proteins in SDS-PAGE, indicating a change in their post-translational modification state. These alterations correlate with a decreased association of STAT5 and RNA polymerase II with STAT5 target genes in chromatin immunoprecipitation assays. Interestingly, expression of STAT5 target genes such as Cis and c-Myc was differentially regulated by α-Br-TMC in normal and cancer cells. While both genes were inhibited in IL-3-stimulated Ba/F3 cells, expression of the oncogene c-Myc was down-regulated and that of the tumor suppressor gene Cis was up-regulated in transformed Ba/F3-1*6 cells. The synthetic chalcone α-Br-TMC might therefore represent a promising novel anticancer agent for therapeutic intervention in STAT5-associated malignancies.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0090275&type=printable |
| spellingShingle | Sophia Pinz Samy Unser Susanne Brueggemann Elisabeth Besl Nafisah Al-Rifai Hermina Petkes Sabine Amslinger Anne Rascle The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway. PLoS ONE |
| title | The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway. |
| title_full | The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway. |
| title_fullStr | The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway. |
| title_full_unstemmed | The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway. |
| title_short | The synthetic α-bromo-2',3,4,4'-tetramethoxychalcone (α-Br-TMC) inhibits the JAK/STAT signaling pathway. |
| title_sort | synthetic α bromo 2 3 4 4 tetramethoxychalcone α br tmc inhibits the jak stat signaling pathway |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0090275&type=printable |
| work_keys_str_mv | AT sophiapinz thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT samyunser thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT susannebrueggemann thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT elisabethbesl thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT nafisahalrifai thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT herminapetkes thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT sabineamslinger thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT annerascle thesyntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT sophiapinz syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT samyunser syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT susannebrueggemann syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT elisabethbesl syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT nafisahalrifai syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT herminapetkes syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT sabineamslinger syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway AT annerascle syntheticabromo2344tetramethoxychalconeabrtmcinhibitsthejakstatsignalingpathway |