The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors

Hedvat, Michael; Huszar, Dennis; Herrmann, Andreas; Gozgit, Joseph M.; Schroeder, Anne; Sheehy, Adam; Buettner, Ralf; Proia, David A.; Kowolik, Claudia; Hong, Xin; Armstrong, Brian; Bebernitz, Geraldine; Weng, Shaobu; Wang, Lin; Ye, Minwei; McEachern, Kristen; Chen, Huawei; Morosini, Deborah; Bell, Kelly; Alimzhanov, Marat; Ioannidis, Stephanos; McCoon, Patricia; Cao, Z. Alexander; Yu, Hua; Jove, Richard; Zinda, Michael

doi:10.1016/j.ccr.2009.10.015

Cited by 479 publications

(473 citation statements)

References 49 publications

(67 reference statements)

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“…A similar anti-tumor effect of Stat3 antisense oligonucleotides was shown in a mouse lymphoma model [79]. Effective inhibition of tumorigenic growth of many different types of cancer www.cell-research.com | Cell Research Guobin He and Michael Karin 165 npg cells transplanted into mice was observed upon treatment with AZD1480, a highly specific JAK2 inhibitor [87].…”

Section: Stat3 As a Therapeutic Target In Human Hccmentioning

confidence: 66%

NF-κB and STAT3 – key players in liver inflammation and cancer

2010

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Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is one of the most deadly human cancers. The pathogenesis of HCC is frequently linked with continuous hepatocyte death, inflammatory cell infiltration and compensatory liver regeneration. Understanding the molecular signaling pathways driving or mediating these processes during liver tumorigenesis is important for the identification of novel therapeutic targets for this dreadful disease. The classical IKKβ-dependent NF-κB signaling pathway has been shown to promote hepatocyte survival in both developing and adult livers. In addition, it also plays a crucial role in liver inflammatory responses by controlling the expression of an array of growth factors and cytokines. One of these cytokines is IL-6, which is best known for its role in the liver acute phase response. IL-6 exerts many of its functions via activation of STAT3, a transcription factor found to be important for HCC development. This review will focus on recent studies on the roles of NF-κB and STAT3 in liver cancer. Interactions between the two pathways and their potential as therapeutic targets will also be discussed.

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Section: Stat3 As a Therapeutic Target In Human Hccmentioning

confidence: 66%

NF-κB and STAT3 – key players in liver inflammation and cancer

2010

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“…To verify that Jak2 and Stat5a/b are critical for Prl induction of EMT in PC cells, we used pharmacological and genetic tools to disrupt Jak2 and Stat5a/b signaling. The Jak2 kinase inhibitor, AZD1480, 64 previously shown to inhibit Stat5a/b signaling in PC cells, 38 suppressed Prl regulation of Jak2 phosphorylation (Supplemental Figure S1A) and E-cadherin, N-cadherin, vimentin, and Twist1 ( Figure 1C 5) and inoculated s.c. into the flanks of nude mice after 24 hours. After 3 weeks, cell surface E-cadherin and nuclear Stat5a/b levels were analyzed by immunohistochemistry (IHC) in paraffin-embedded tissue sections.…”

Section: Jak2-stat5a/b Signaling Induces Expression Of Emt Markers Inmentioning

confidence: 89%

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

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Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/beinduced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stemlike properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells. Most prostate cancer (PC)erelated deaths are because of development of metastatic disease. A central process in metastatic dissemination of PC is epithelial-to-mesenchymal transition (EMT), during which cancer cells attain more motile and invasive properties, invade through the basement membrane, and survive in systemic circulation. 1e3 Extravasation at distant organ sites is followed by adhesion of cancer cells to extracellular matrix proteins, such as fibronectin, 4e6 leading to formation of premetastatic niches and subsequent formation of macroscopic metastases. 7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter

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“…DU145 cells are a model of androgen receptor (AR) negative and androgen-independent prostate cancer. Furthermore, unlike the AR-dependent LNCaP cells, DU145 cells have constitutive activation of both STAT3 and NF-kB (30,44,45). These cells represent also a good model of prostate tumors characterized by concomitant upregulation of ESE1/ELF3 and sustained activation of NF-kB (35).…”

Section: Ec-70124 Inhibits Nf-kb and Stat3 In Prostate Cancer Cellsmentioning

confidence: 99%

“…Inhibition of NF-kB and STAT3 individually is known to affect proliferation of DU145 cells (30,44,46,47). Given the ability of EC-70124 to block concomitantly both signaling pathways, we examined the compound's effect on the phenotype of DU145 cells.…”

Section: Ec-70124 Affects Proliferation Of Prostate Cancer Cellsmentioning

confidence: 99%

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

Civenni

Longoni

Costales

et al. 2016

Molecular Cancer Therapeutics

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Cancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-kB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKb and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-kB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKb and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-kB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo. Thus, EC-70124 is a potent inhibitor of the NF-kB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806-18. Ó2016 AACR.

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The JAK2 Inhibitor AZD1480 Potently Blocks Stat3 Signaling and Oncogenesis in Solid Tumors

Cited by 479 publications

References 49 publications

NF-κB and STAT3 – key players in liver inflammation and cancer

NF-κB and STAT3 – key players in liver inflammation and cancer

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

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