Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

Hover, Laura D.; Young, Christian D.; Bhola, Neil E.; Wilson, Andrew J.; Khabele, Dineo; Hong, Charles C.; Moses, Harold L.; Owens, Philip

doi:10.1016/j.canlet.2015.07.032

Cited by 31 publications

(28 citation statements)

References 72 publications

(89 reference statements)

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“…We also used a small-molecule inhibitor of BMP signaling, DMH1, to block pathway activity. DMH1 can suppress the growth of BMP-dependent ovarian and lung cancer cells (36,37), but its efficacy in melanoma has not been reported. DMH1 inhibits the kinase activity of ALK2 and BMPR1A (ALK3) receptors but not of BMPR1B (ALK6), thereby abrogating phosphorylation and activation of the SMAD1/5/8 transcriptional cascade (38).…”

Section: Resultsmentioning

confidence: 99%

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Venkatesan¹,

Vyas²,

Gramann³

et al. 2017

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Venkatesan¹,

Vyas²,

Gramann³

et al. 2017

Journal of Clinical Investigation

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“…We used a CRISPR (clustered regularly interspaced short palindromic repeat)-screen dataset from ten cell lines of various tissue types to identify HGSC-specific essential genes (Hart et al, 2015). Inspection of genes with a high frequency of essentiality, as well as high expression in HGSC cell lines and tumors, confirmed known proto-oncogenic targets in ovarian cancer, including ERBB3, EPHB4, and BMPR1A, which contribute to cell survival and chemotherapeutic resistance (Hover et al, 2015;Kumar et al, 2007;Sheng et al, 2010). Our integrated (C-E) Expression and essentiality of (C) receptor tyrosine kinases (RTKs) and serine/threonine kinases (STKs), (D) tetraspanins and integrins, and (E) G-proteincoupled receptors (GPCRs) in HGSC cell lines and TCGA tumors.…”

Section: Functional Surfaceome Of Hgscmentioning

confidence: 99%

Interrogation of Functional Cell-Surface Markers Identifies CD151 Dependency in High-Grade Serous Ovarian Cancer

et al. 2017

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The degree of genetic aberrations characteristic of high-grade serous ovarian cancer (HGSC) makes identification of the molecular features that drive tumor progression difficult. Here, we perform genome-wide RNAi screens and comprehensive expression analysis of cell-surface markers in a panel of HGSC cell lines to identify genes that are critical to their survival. We report that the tetraspanin CD151 contributes to survival of a subset of HGSC cell lines associated with a ZEB transcriptional program and supports the growth of HGSC tumors. Moreover, we show that high CD151 expression is prognostic of poor clinical outcome. This study reveals cell-surface vulnerabilities associated with HGSC, provides a framework for identifying therapeutic targets, and reports a role for CD151 in HGSC.

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“…These newer molecules specifically target BMP signaling but not VEGF and angiogenesis 19 . DMH1 has been shown to promote cardiac differentiation in mouse embryonic stem cells 38 and facilitate neurogenesis of human-induced pluripotent stem cells 39 , and inhibit ovarian cancer cell growth 40 . In this study, we found that DMH1 significantly inhibited Pi and BMP2-induced calcium deposition in HASMCs as revealed by Alizarin Red S staining and calcium assay.…”

Section: Discussionmentioning

confidence: 99%

Dorsomorphin homologue 1, a highly selective small-molecule bone morphogenetic protein inhibitor, suppresses medial artery calcification

Lin

Wang

Zettervall

et al. 2017

Journal of Vascular Surgery

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Medial artery calcification develops in diabetes, chronic kidney disease, and as part of the aging process. It is associated with increased morbidity and mortality in vascular patients. Bone morphogenetic proteins (BMPs) have previously been implicated in the initiation and progression of vascular calcification. We thus evaluated whether DMH1, a highly specific BMP inhibitor, could attenuate vascular calcification in vitro and in an organ culture model of medial calcification. Methods Confluent human aortic smooth muscle cells (HASMCs) were cultured in calcification medium containing 3.0 mM inorganic phosphate (Pi) for 7 days with or without DMH1. Medial calcification was assessed using an aortic organ culture model. Calcification was visualized by Alizarin Red S staining, and calcium concentration was assessed by an o-cresolphthalein complexone calcium assay. Osteogenic cell and vascular smooth muscle cell (SMC) markers were determined by Western blot, qRT-PCR and immunohistochemistry staining. Results DMH1 reduced Pi-induced calcium deposition in human SMCs. It also antagonized human recombinant BMP2-induced calcium accumulation. Western blot further revealed that DMH1 was able to block Pi-mediated up-regulation of osteoblast markers including osterix and alkaline phosphatase (ALP), and down-regulation of SMC markers such as smooth muscle cell markers myosin heavy chain (SM-MHC) and SM22α, as well as P-Smad1/5/8, suggesting that DMH1 may regulate SMC osteogenic differentiation via the BMP/Smad1/5/8 signal pathway. Finally, utilizing an ex vivo aortic ring organ culture model, we observed that DMH1 has an ability to reduce Pi-induced aortic medial calcification. Conclusions The selective BMP inhibitor DMH1 can inhibit calcium accumulation in vascular smooth muscle cells and arterial segments exposed to elevated phosphate levels. Such small molecules may have clinical utility in reducing medial artery calcification in our vascular patient population.

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Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

Cited by 31 publications

References 72 publications

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Interrogation of Functional Cell-Surface Markers Identifies CD151 Dependency in High-Grade Serous Ovarian Cancer

Dorsomorphin homologue 1, a highly selective small-molecule bone morphogenetic protein inhibitor, suppresses medial artery calcification

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