Pharmaceutical intervention in the JAK/STAT signaling pathway

Hm, Seidel; Lamb, Peter; Rosen, Jonathan

doi:10.1038/sj.onc.1203550

Cited by 84 publications

(50 citation statements)

References 64 publications

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“…Activated cytokine receptors provide scaffolds upon which STATs are phosphorylated by Janus Kinases (JAKs) (Seidel et al, 2000), whereupon STATs translocate to the nucleus and upregulate the expression of target genes, including those for numerous cytokines (Kotenko and Pestka, 2000;Reddy et al, 2000). STAT3 plays a role in driving proliferation and counteracting differentiation signals (Bowman et al, 2000;Bromberg and Darnell, 2000), and a STAT3 mutant that dimerizes in the absence of tyrosine phosphorylation is constitutively active and functions as an oncogene (Bromberg et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3

et al. 2004

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Cell growth is promoted by mitogens and survival factors, which activate intracellular signalling pathways to control cell cycle progression and cellular integrity. Proliferation signals are transmitted through Ras and Rho family small G-proteins coupled to mitogen-activated protein kinase (MAPK) cascades, while survival signals are propagated by lipid-dependent kinases such as phosphatidylinositide 3-kinases (PI3Ks) and protein kinase B (Akt/PKB). Recently, signal transducer and activator of transcription (STAT) proteins were identified as positive regulators of proliferation in a variety of cell types. Persistent activation of these pathways is associated with tumour cell growth, whereas their inhibition can halt proliferation and precipitate apoptotic cell death. The human pathogen Pseudomonas aeruginosa uses quorum-sensing signal molecules (QSSMs) to regulate virulence gene expression. QSSMs also suppress host immune responses although the mechanism of suppression is unknown. Here, we demonstrate that the QSSM N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) from P. aeruginosa blocks proliferation and induces apoptosis in human BC cell lines. Analyses of signalling events reveal that OdDHL has little or no effect on MAPK cascades, partially inhibits the Akt/PKB pathway and ablates STAT3 activity. Pharmacological inhibition of each pathway independently indicates that STAT3 activity is critical for BC cell proliferation and survival, while a constitutively active STAT3 confers resistance to OdDHL. These results support the notion of OdDHL as a bioactive molecule in eukaryotic systems and a paradigm for a novel class of antiproliferative compounds.

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Section: Introductionmentioning

confidence: 99%

Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3

et al. 2004

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“…The potentially important role of STAT proteins in a number of human cancers makes them prime candidates for therapeutic intervention (Bowman et al, 2000;Seidel et al, 2000). In vitro models have shown that dominantnegative forms of STAT3 or STAT5 can inhibit cellular proliferation and transformation.…”

Section: Stats As Therapeutic Targetsmentioning

confidence: 99%

Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis

2004

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“…While these studies present some preliminary observations implicating abnormal STAT signaling in the pathogenesis of these diseases, it is essential to validate the key role of constitutive STAT signaling in order to assess the therapeutic usefulness of anti-Stat3 intervention for each disease type. Moreover, the important role of JAK-STAT signaling in many fundamental biological processes provides basis for evaluating the target validity in human disease cases where abnormal JAKs or STATs are observed (Frank, 1999;Lin et al, 2000;Seidel et al, 2000).…”

Section: Stat3 Activation and Human Diseasesmentioning

confidence: 99%

“…The potential of this approach has been demonstrated using the IL-6 superantagonist', Sant7, that blocks constitutive Stat3 activation in U266 myeloma cells (Catlett-Falcone et al, 1999b) and inhibits cell growth (Demartis et al, 1996;Petrucci et al, 1999). Moreover, current clinical applications of this approach in certain types of human disease conditions, including the use of recombinant tissue necrosis factor receptor in treatment of rheumatoid arthritis (Moreland et al, 1997; for review, see Seidel et al, 2000), make a compelling argument for evaluating its usefulness for cancer therapy. However, considerably more studies remain to be done to show the correlation of growth inhibition of tumors in whole animals with block of constitutive Stat3 activity using receptor or ligand antagonists.…”

Section: Strategies For Targeting Stat3 For Drug Discoverymentioning

confidence: 99%