Small molecule antagonist of the bone morphogenetic protein type I receptors suppresses growth and expression of Id1 and Id3 in lung cancer cells expressing Oct4 or nestin

Langenfeld, Elaine; Deen, Malik; Zachariah, Emmanuel; Langenfeld, John

doi:10.1186/1476-4598-12-129

Cited by 32 publications

(24 citation statements)

References 60 publications

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“…37 Inhibiting BMP signaling also decreases Id1 (and Id3) protein expression; thus, small-molecule BMP type I receptor antagonists may represent a novel way of targeting Id-expressing cancer cells. 38 Regardless of which strategy is pursued, the successful clinical development of an Id1 inhibitor will require much additional work. Given that CBD made AML cells more sensitive to an AKT inhibitor, and vice versa, combining Id1 inhibitors with AKT inhibitors or other inhibitors of cell signaling could be a promising therapeutic strategy for AML patients.…”

Section: Discussionmentioning

confidence: 99%

Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression

Wang

Man

Sun

et al. 2015

Blood

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• Using genetically modified mice, we identified the crucial role of Id1 in t(8;21) leukemogenesis through regulating AKT signaling.• Id1 inhibitor has a significant therapeutic effect in the mouse model of t(8;21) leukemia.Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a pivotal role in acute myeloid leukemogenesis. Using genetically modified mice, we found that loss of Id1 inhibited t(8;21) leukemia initiation and progression in vivo by abrogating protein kinase B (AKT)1 activation, and that Id1 interacted with AKT1 through its C terminus. An Id1 inhibitor impaired the in vitro growth of AML cells and, when combined with an AKT inhibitor, triggered even greater apoptosis and growth inhibition, whereas normal hematopoietic stem/ progenitor cells were largely spared. We then performed in vivo experiments and found that the Id1 inhibitor significantly prolonged the survival of t(8;21) 1 leukemic mice, whereas overexpression of activated AKT1 promoted leukemogenesis. Thus, our results establish Id1/ Akt1 signaling as a potential therapeutic target in t(8;21) leukemia. (Blood. 2015;126(5):640-650)

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Section: Discussionmentioning

confidence: 99%

Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression

Wang

Man

Sun

et al. 2015

Blood

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“…Recent genetic studies have implicated that RBFOX3 is involved in numerous neurological dysfunctions in humans, such as the development of autistic features, epilepsy, cognitive impairments, and neurodevelopmental delay. Although previous studies reported RBFOX3 was exclusively expressed in post-mitotic neurons of the central nervous system, recent studies indicated that RBFOX3 is also expressed in some non-neuronal tissues [30, 31]. Another study showed that RBFOX3 expression was inhibited during TGF-β-induced epithelial-mesenchymal transition (EMT) in lung cancer [32].…”

Section: Discussionmentioning

confidence: 99%

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

Liu¹,

Wu²,

Li³

et al. 2018

Cell Physiol Biochem

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Background/Aims: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown. Methods: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model. Results: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models. Conclusions: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.

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“…Blocking BMP signaling by DMH1 may interrupt lung cancer stem cell growth, thus suppressing tumor progression. This hypothesis is supported by a very recent study that inhibition of BMP signaling suppressed growth of the population of lung cancers cells expressing stem cell markers [22]. In addition, it has been reported from multiple studies that BMP-activated Smad signaling or the Id gene family have the potential to promote migration and invasion in different types of cancer [18], [23], [24].…”

Section: Discussionmentioning

confidence: 76%

DMH1, a Small Molecule Inhibitor of BMP Type I Receptors, Suppresses Growth and Invasion of Lung Cancer

et al. 2014

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The bone morphogenetic protein (BMP) signaling cascade is aberrantly activated in human non-small cell lung cancer (NSCLC) but not in normal lung epithelial cells, suggesting that blocking BMP signaling may be an effective therapeutic approach for lung cancer. Previous studies demonstrated that some BMP antagonists, which bind to extracellular BMP ligands and prevent their association with BMP receptors, dramatically reduced lung tumor growth. However, clinical application of protein-based BMP antagonists is limited by short half-lives, poor intra-tumor delivery as well as resistance caused by potential gain-of-function mutations in the downstream of the BMP pathway. Small molecule BMP inhibitors which target the intracellular BMP cascades would be ideal for anticancer drug development. In a zebrafish embryo-based structure and activity study, we previously identified a group of highly selective small molecule inhibitors specifically antagonizing the intracellular kinase domain of BMP type I receptors. In the present study, we demonstrated that DMH1, one of such inhibitors, potently reduced lung cell proliferation, promoted cell death, and decreased cell migration and invasion in NSCLC cells by blocking BMP signaling, as indicated by suppression of Smad 1/5/8 phosphorylation and gene expression of Id1, Id2 and Id3. Additionally, DMH1 treatment significantly reduced the tumor growth in human lung cancer xenograft model. In conclusion, our study indicates that small molecule inhibitors of BMP type I receptors may offer a promising novel strategy for lung cancer treatment.

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Small molecule antagonist of the bone morphogenetic protein type I receptors suppresses growth and expression of Id1 and Id3 in lung cancer cells expressing Oct4 or nestin

Cited by 32 publications

References 60 publications

Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression

Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

DMH1, a Small Molecule Inhibitor of BMP Type I Receptors, Suppresses Growth and Invasion of Lung Cancer

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