The Synthetic α-Bromo-2′,3,4,4′-Tetramethoxychalcone (α-Br-TMC) Inhibits the JAK/STAT Signaling Pathway

Pinz, Sophia; Unser, Samy; Brueggemann, Susanne; Besl, Elisabeth; Al-Rifai, Nafisah; Petkes, Hermina; Amslinger, Sabine; Rascle, Anne

doi:10.1371/journal.pone.0090275

Cited by 23 publications

(36 citation statements)

References 84 publications

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“…Ba/F3-1*6 and K562 cells were also treated with 1 µM Imatinib, as a positive control for pSTAT5 inhibition in K562 cells. The BCR-ABL inhibitor Imatinib drastically and specifically inhibited STAT5 phosphorylation in K562 cells (Figure 4C), as previously reported [56], [74]. In agreement with our previous data in Ba/F3 cells [21], TSA did not affect STAT5 phosphorylation in any of the three cell lines (Figure 4A–C).…”

Section: Resultssupporting

confidence: 92%

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The Natural Chemopreventive Agent Sulforaphane Inhibits STAT5 Activity

2014

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Signal transducer and activator of transcription STAT5 is an essential mediator of cytokine, growth factor and hormone signaling. While its activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated to a number of hematological and solid tumor cancers. We previously showed that deacetylase inhibitors can inhibit STAT5 transcriptional activity. We now investigated whether the dietary chemopreventive agent sulforaphane, known for its activity as deacetylase inhibitor, might also inhibit STAT5 activity and thus could act as a chemopreventive agent in STAT5-associated cancers. We describe here sulforaphane (SFN) as a novel STAT5 inhibitor. We showed that SFN, like the deacetylase inhibitor trichostatin A (TSA), can inhibit expression of STAT5 target genes in the B cell line Ba/F3, as well as in its transformed counterpart Ba/F3-1*6 and in the human leukemic cell line K562 both of which express a constitutively active form of STAT5. Similarly to TSA, SFN does not alter STAT5 initial activation by phosphorylation or binding to the promoter of specific target genes, in favor of a downstream transcriptional inhibitory effect. Chromatin immunoprecipitation assays revealed that, in contrast to TSA however, SFN only partially impaired the recruitment of RNA polymerase II at STAT5 target genes and did not alter histone H3 and H4 acetylation, suggesting an inhibitory mechanism distinct from that of TSA. Altogether, our data revealed that the natural compound sulforaphane can inhibit STAT5 downstream activity, and as such represents an attractive cancer chemoprotective agent targeting the STAT5 signaling pathway.

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Section: Resultssupporting

confidence: 92%

“…Antibodies used for the detection of pSTAT5, STAT5A, STAT5B, STAT5A+B, α-tubulin, Anti-Rabbit and Anti-Mouse IgG-Peroxidase, as well as their respective working dilutions, have been reported [56].…”

Section: Methodsmentioning

confidence: 99%

The Natural Chemopreventive Agent Sulforaphane Inhibits STAT5 Activity

2014

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“…The IL-3-dependent mouse pro-B cell line Ba/F3 (a kind gift from Jacqueline Marvel, IFR 128 BioSciences Gerland-Lyon Sud, France) ( 65 ) was grown in RPMI 1640 (PAN-Biotech P04–16500) supplemented with 10% heat-inactivated fetal calf serum (FCS; PAN-Biotech), 1% penicillin/streptomycin (PAN-Biotech) and 2 ng/ml rmIL-3 (ImmunoTools). The IL-3-independent Ba/F3–1*6 cell line (clone F7) stably expressing the constitutively active (FLAG-tagged) mouse STAT5A-1*6 mutant ( 66 ) has been recently described ( 36 ) and was grown in RPMI 1640 supplemented with 10% heat-inactivated FCS, 1% penicillin/streptomycin and 600 μg/ml G418 (SIGMA A-1720). The Ba/F3-tet-on-1*6 cell line was generated by stably transfecting Ba/F3 cells with the pTet-On Advanced vector (Clontech) expressing the rtTA-Advanced transactivator under neomycin (G418) selection.…”

Section: Methodsmentioning

confidence: 99%

Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function

Pinz

Unser

Buob

et al. 2015

Nucleic Acids Research

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Signal transducer and activator of transcription STAT5 is essential for the regulation of proliferation and survival genes. Its activity is tightly regulated through cytokine signaling and is often upregulated in cancer. We showed previously that the deacetylase inhibitor trichostatin A (TSA) inhibits STAT5-mediated transcription by preventing recruitment of the transcriptional machinery at a step following STAT5 binding to DNA. The mechanism and factors involved in this inhibition remain unknown. We now show that deacetylase inhibitors do not target STAT5 acetylation, as we initially hypothesized. Instead, they induce a rapid increase in global histone acetylation apparently resulting in the delocalization of the bromodomain and extra-terminal (BET) protein Brd2 and of the Brd2-associated factor TBP to hyperacetylated chromatin. Treatment with the BET inhibitor (+)-JQ1 inhibited expression of STAT5 target genes, supporting a role of BET proteins in the regulation of STAT5 activity. Accordingly, chromatin immunoprecipitation demonstrated that Brd2 is associated with the transcriptionally active STAT5 target gene Cis and is displaced upon TSA treatment. Our data therefore indicate that Brd2 is required for the proper recruitment of the transcriptional machinery at STAT5 target genes and that deacetylase inhibitors suppress STAT5-mediated transcription by interfering with Brd2 function.

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“…Still it was the first experimental tool to target STAT5 in clinically relevant cell systems. A current study identifies the synthetic chalone α-Br-TMC as an inhibitor of JAK2/STAT5 signaling [ 57 ]. Although, cytotoxic effects are only observed at high concentrations (100 μM) in cells expressing cSTAT5, tyrosine phosphorylation of STAT5 and JAK2 was strongly reduced at 10 μM.…”

Section: Blocking Stat5 Nuclear Translocationmentioning

confidence: 99%

Inhibition of STAT5: A therapeutic option in BCR-ABL1-driven leukemia

et al. 2014

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The two transcription factors STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases and they fulfill all criteria of drug targets. STAT5A and STAT5B display unique nuclear shuttling mechanisms and they have a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). Moreover, STAT5A and STAT5B promote survival of leukemic stem cells. We here discuss the possibility of targeting up-stream kinases with TKI, direct STAT5 inhibition via SH2 domain obstruction and blocking nuclear translocation of STAT5. All discussed options will result in a stop of STAT5 transport to the nucleus to block STAT5-mediated transcriptional activity. In summary, recently described shuttling functions of STAT5 are discussed as potentially druggable pathways in leukemias.

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The Synthetic α-Bromo-2′,3,4,4′-Tetramethoxychalcone (α-Br-TMC) Inhibits the JAK/STAT Signaling Pathway

Cited by 23 publications

References 84 publications

The Natural Chemopreventive Agent Sulforaphane Inhibits STAT5 Activity

The Natural Chemopreventive Agent Sulforaphane Inhibits STAT5 Activity

Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function

Inhibition of STAT5: A therapeutic option in BCR-ABL1-driven leukemia

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