Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-β Type I Receptor Kinase<i>In vivo</i>

Ge, Rongrong; Rajeev, Vaishali; Ray, Partha S.; Lattime, Edmund C.; Rittling, Susan R.; Medicherla, Satyanarayana; Protter, Andy; Murphy, Alison; Chakravarty, Jit; Dugar, Sundeep; Schreiner, George F.; Barnard, Nicola; Reiß, Michael

doi:10.1158/1078-0432.ccr-06-0162

Cited by 130 publications

(110 citation statements)

References 77 publications

(62 reference statements)

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“…TGFβ (100 pM) activates Smad2 and Smad3 with an expected early response peaking at 2 hr. The selective TβRI kinase inhibitor, SD208, which inhibits the phosphorylation/activation of Smad2 and Smad3, 62 obviated TGFβ-mediated growth inhi bition. Smad2 and Smad3 elicit Figure 4.…”

Section: Discussionmentioning

confidence: 99%

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Lecanda

Ganapathy²,

D'Aquino-Ardalan³

et al. 2009

Cell Cycle

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TGFβ mediates cell cycle arrest in late G 1 phase of the cell cycle with a simultaneous peak in the levels of the cyclin-dependent kinase inhibitor, p27 kip1 (p27). In this report, we show that whereas p27 resides in the cytoplasm in the endometrial carcinoma (ECA) cell line HEC-1A, TGFβ increases the total levels and translocation of p27 into the nucleus. Concomitantly, TGFβ activates the transcription factors Smad2 and Smad3, inhibits proliferation, and blocks Cdk2 activity; all these events are blocked by an inhibitor of TβRI serine kinase activity (SD208). In addition, we show that inhibiting p27 transcription with a specific siRNA completely blocks TGFβ-mediated growth inhibition in these cells. These data suggest that TGFβ inhibits cellular proliferation by increasing p27 levels through Smad2/3 signaling in HEC-1A cells. We further show that TGFβ decreases the levels of components of the SCF Skp2 targeting complex for ubiquitin-mediated degradation of p27 in proteasomes, at the protein but not the mRNA level. Therefore, TGFβ accumulates nuclear p27 by preventing its degradation to enable G 1 arrest in HEC-1A cells. Importantly, these data suggest a novel mechanism for TGFβ/Smad mediated growth inhibition that might be inoperable in the numerous human cancers demonstrating early dysregulated TGFβ signaling and loss of growth inhibition. The TGFβ/p27 axis might provide novel therapeutic targets for cancer.

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Section: Discussionmentioning

confidence: 99%

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Lecanda

Ganapathy²,

D'Aquino-Ardalan³

et al. 2009

Cell Cycle

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“…These compounds often compete with binding of ATP to the ATP-binding site of the kinase, and several of them inhibit the TbRI kinase selectively, but often also inhibit the activin type I receptor ALK-4 and the nodal type I receptor ALK-7 (Yingling et al 2004). TbRI kinase inhibitors have been shown, in animal models, to inhibit invasion and metastasis of, for example, breast cancer cells (Bandyopadhyay et al 2006;Ge et al 2006;Ehata et al 2007;Liu et al 2012), melanoma cells (Mohammad et al 2011), glioma cells (Uhl et al 2004;Zhang et al 2011), and mesothelioma cells (Suzuki et al 2007). The effect of the inhibitors include inhibition of mesenchymal transition of the tumor cells, activation of the immune system, inhibition of angiogenesis, inhibition of osteolysis preventing bone metastasis, and normalization of tumor stroma.…”

Section: Tgf-b Family Receptorsmentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

524

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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“…(14) For example, SB-431542, SD-208 and SM16 are small molecules that block the catalytic activity of TbRI and have been reported to be potent antitumor or antimetastatic agents. (15)(16)(17) It has also been reported that neutralizing antibody against TGF-b ligand has a suppressive effect on lung metastasis, (18) and that a Smad-binding peptide aptamer inhibits TGF-b signalling and EMT. (19) To determine whether the targeting of ALK5 offers an effective therapeutic approach to the suppression of breast cancer metastasis, we examined the effects of the novel ALK5 inhibitor EW-7203 (3-((5-( [1,2,4]triazolo [1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)thiazol-2-ylamino)methyl)benzonitrile) on motility, Smad signalling and EMT in NMuMG and MCF10A cells in vitro and on the development of metastasis in vivo using an orthotopic xenograft model.…”

mentioning

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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Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-β Type I Receptor KinaseIn vivo

Cited by 130 publications

References 77 publications

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Signaling Receptors for TGF-β Family Members

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

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