Selective inhibitors of type I receptor kinase block cellular transforming growth factor-β signaling

Ge, Rongrong; Rajeev, Vaishali; Subramanian, Gayathri; Reiss, Kim A.; Liu, David; Higgins, Linda S.; Joly, Alison; Dugar, Sundeep; Chakravarty, Jit; Henson, Margaret; McEnroe, Glenn; Schreiner, George F.; Reiß, Michael

doi:10.1016/j.bcp.2004.03.011

Cited by 38 publications

(28 citation statements)

References 39 publications

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“…Recently, Ge and colleagues published similar results for a different TbRI kinase inhibitor, SD-093. (29) TGF-b1-induced EMT plays important roles in the progression of both cancer and chronic renal disease. In cancer, EMT generally predicts a more aggressive tumor cell behavior.…”

Section: Discussionmentioning

confidence: 99%

EW‐7203, a novel small molecule inhibitor of transforming growth factor‐β (TGF‐β) type I receptor/activin receptor‐like kinase‐5, blocks TGF‐β1‐mediated epithelial‐to‐mesenchymal transition in mammary epithelial cells

2011

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Recently, small molecule inhibitors of transforming growth factorb (TGF-b) type I receptor kinase ⁄ activin receptor-like kinase-5 (ALK5) have been developed to target TGF-b signalling as a therapeutic strategy for combating cancer. In the present study, the authors examined a novel small molecule inhibitor of ALK5,[3][4][5]2,4]triazolo [1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)thiazol-2-ylamino)methyl)benzonitrile (EW-7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW-7203 on TGF-b-induced Smad signalling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7203 on mammary cancer metastasis to the lung were examined using a Balb ⁄ c xenograft model system. The novel ALK5 inhibitor, EW-7203, inhibited the TGF-b1-stimulated transcriptional activation of p3TP-Lux and pCA-GA 12 -Luc. In addition, EW-7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF-b1. In addition, EW-7203 inhibited TGF-b1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb ⁄ c mice, EW-7203 inhibited metastasis to the lung from breast tumors. The novel ALK5 inhibitor, EW-7203, efficiently inhibited TGF-b1-induced Smad signalling, EMT and breast tumor metastasis to the lung in vivo, demonstrating that EW-7203 has therapeutic potential for breast cancer metastasis to the lung. (Cancer Sci 2011; 102: 1889-1896 M etastasis is the primary cause of death among cancer patients, and breast cancer patients are no exception.(1,2) During breast cancer progression, transforming growth factor-b (TGF-b) levels are elevated (3,4) and the tumor-suppressing function of TGF-b is abrogated.(5) Transforming growth factor-b has at least two roles during carcinogenesis, for although it was initially found to be a tumor-suppressing cytokine, it also acts as a mediator of metastasis to the lung.(6,7) During the initial stage of metastasis, cancer cells undergo epithelial-to-mesenchymal transition (EMT), which involves loss of epithelial cell polarity, acquisition of the mesenchymal phenotype, greater motility and invasiveness, and disruption of cell-to-cell adhesion. The EMT is generally induced in epithelial cells by signals released from mesenchymal cells that compose the stroma of normal and neoplastic tissues. Furthermore, members of the TGF-b cytokine family are the foremost characterized inducers of EMT during embryonic development, wound healing, fibrotic diseases and cancer pathogenesis, (7,9) which suggests that TGFb might induce EMT via multiple signalling mechanisms. The canonical TGF-b signalling pathway is activated when TGF-b binds to TGF-b type II receptor (TbRII). Initially, this binding facilitates activation of TGF-b type I receptor (TbRI) kinase (activin receptor-like kinase 5 [ALK5]), (10) which contains a kinase domain that phospho...

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Section: Discussionmentioning

confidence: 99%

EW‐7203, a novel small molecule inhibitor of transforming growth factor‐β (TGF‐β) type I receptor/activin receptor‐like kinase‐5, blocks TGF‐β1‐mediated epithelial‐to‐mesenchymal transition in mammary epithelial cells

2011

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“…Thus, EMT in cancer cells describes merely one manifestation in the context of a spectrum of inter-related, fundamentally different and permanent reprogramming of cellular behaviors that is intrinsic to malignant cells. A growing number of in vivo studies demonstrate that inhibitors of TGF-b or TGF-b receptors may reduce the metastatic and/or invasive properties of a variety of experimental cancers presumably by preventing activation of EMT pathways (Dumont and Arteaga, 2003;Ge et al, 2004;Subramanian et al, 2004;Yingling et al, 2004). Thus, there is broad experimental support for an important role of TGF-b in oncogenic EMT associated with cancer progression, in particular in cooperation with oncogenic Ras (Derynck et al, 2001;Dumont and Arteaga, 2003;Roberts and Wakefield, 2003;Gotzmann et al, 2004).…”

Section: Physiological Context Defines Distinct Roles and Features Ofmentioning

confidence: 99%

TGF-β and epithelial-to-mesenchymal transitions

2005

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Remarkable phenotype plasticity of epithelial cells underlies morphogenesis, epithelial repair and tumor invasiveness. Detailed understanding of the contextual cues and molecular mediators that control epithelial plasticity will be required in order to develop viable therapeutic approaches targeting epithelial-to-mesenchymal transition (EMT), an advanced manifestation of epithelial plasticity. Members of the transforming growth factor (TGF-b) family of growth factors can initiate and maintain EMT in a variety of biological systems and pathophysiological context by activating major signaling pathways and transcriptional regulators integrated in extensive signaling networks. Here we will review the distinct physiological contexts of EMT and the underlying molecular signaling networks controlled by TGF-b.

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“…To test this hypothesis, we made use of potent and selective chemical inhibitors of the T R-I kinase, which allowed us to conduct precisely controlled T R-I activity "knock-down" experiments [21,22]. We have shown previously that these agents are capable of inhibiting TGF -mediated Smad phosphorylation, target gene expression, cell cycle arrest, EMT, and cell motility in a dose-dependent manner [22,23].…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor-β Signaling Strength Determines Target Gene Expression Profile in Human Keratinocytes

Kareddula¹,

Zachariah²,

Notterman³

et al. 2008

JEBP

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Transforming Growth Factor-(TGF ) maintains keratinocyte homeostasis, and induces epithelial-tomesenchymal transition (EMT) in response to tissue injury. To investigate how these two TGF responses might become uncoupled during malignant transformation, we examined the TGF -regulated gene expression programs and cellular responses in human keratinocytes as a function of TGF type I receptor (T R-I) kinase activity and TGF level. The TGFmediated homeostatic gene response program and cellular growth arrest were extremely sensitive to a reduction in receptor kinase activity, while much stronger inhibition of TGF receptor activity was needed to inhibit the tissue injury response gene expression program and EMT. Both endogenous TGF and high exogenous levels of TGF induced the homeostatic response, while only high levels of TGF induced EMT. These results suggest that a reduction in receptor signaling activity may be sufficient for keratinocytes to escape from TGF 's tumor suppressor function, while higher levels of TGF associated with tumor progression are pro-invasive/metastatic. These findings have important implications for the optimal use of TGF /Smad signaling antagonists as anti-cancer therapeutics.

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Selective inhibitors of type I receptor kinase block cellular transforming growth factor-β signaling

Cited by 38 publications

References 39 publications

EW‐7203, a novel small molecule inhibitor of transforming growth factor‐β (TGF‐β) type I receptor/activin receptor‐like kinase‐5, blocks TGF‐β1‐mediated epithelial‐to‐mesenchymal transition in mammary epithelial cells

EW‐7203, a novel small molecule inhibitor of transforming growth factor‐β (TGF‐β) type I receptor/activin receptor‐like kinase‐5, blocks TGF‐β1‐mediated epithelial‐to‐mesenchymal transition in mammary epithelial cells

TGF-β and epithelial-to-mesenchymal transitions

Transforming Growth Factor-β Signaling Strength Determines Target Gene Expression Profile in Human Keratinocytes

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