Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1)<i>via</i>siRNA-induced cell death in glioblastoma

Serban, F; Daianu, Oana; Tătăranu, Ligia Gabriela; Artene, Ştefan-Alexandru; Emami, Ghazaleh Hooshyar; Georgescu, Ada Maria; Alexandru, Oana; Purcaru, Ștefana Oana; Tache, Daniela Elise; Danciulescu, Maria Mihaela; Sfredel, Veronica; Dricu, Anica

doi:10.1080/15321819.2016.1209217

Cited by 18 publications

(17 citation statements)

References 25 publications

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“…ADGRL4/ELTD1 is not expressed by the majority of cancer cell lines [9]. However, it is expressed by glioblastomas where it possibly functions in a different way and is important for tumour survival, and is an emerging therapeutic target in this tumour type [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile

et al. 2019

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Adhesion G Protein-Coupled Receptor L4 (ADGRL4/ELTD1) is an endothelial cell adhesion G protein-coupled receptor (aGPCR) which regulates physiological and tumour angiogenesis, providing an attractive target for anti-cancer therapeutics. To date, ADGRL4/ELTD1′s full role and mechanism of function within endothelial biology remains unknown, as do its ligand(s). In this study, ADGRL4/ELTD1 silencing, using two independent small interfering RNAs (siRNAs), was performed in human umbilical vein endothelial cells (HUVECS) followed by transcriptional profiling, target gene validation, and metabolomics using liquid chromatography-mass spectrometry in order to better characterise ADGRL4/ELTD1′s role in endothelial cell biology. We show that ADGRL4/ELTD1 silencing induced expression of the cytoplasmic metabolic regulator ATP Citrate Lyase (ACLY) and the mitochondria-to-cytoplasm citrate transporter Solute Carrier Family 25 Member 1 (SLC25A1) but had no apparent effect on pathways downstream of ACLY (fatty acid and cholesterol synthesis or acetylation). Silencing induced KIT expression and affected the Notch signalling pathway, upregulating Delta Like Canonical Notch Ligand 4 (DLL4) and suppressing Jagged Canonical Notch Ligand 1 (JAG1) and Hes Family BHLH Transcription Factor 2 (HES2). The effect of ADGRL4/ELTD1 silencing on the cellular metabolic profile was modest but several metabolites were significantly affected. Cis-aconitic acid, uridine diphosphate (UDP)-glucoronate, fructose 2,6-diphosphate, uridine 5-diphosphate, and aspartic acid were all elevated as a result of silencing and phosphocreatine, N-acetylglutamic acid, taurine, deoxyadenosine triphosphate, and cytidine monophosphate were depleted. Metabolic pathway analysis implicated ADGRL4/ELTD1 in pyrimidine, amino acid, and sugar metabolism. In summary, this study shows that ADGRL4/ELTD1 impacts core components of endothelial metabolism and regulates genes involved in endothelial differentiation/homeostasis and Notch signalling.

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Section: Introductionmentioning

confidence: 99%

ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile

et al. 2019

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“…Through a global microarray meta-analysis (GAMMA), 39 we identified ELTD1, an angiogenic marker, to be highly expressed in high-grade gliomas and other groups have suggested that high ELTD1 expression levels may correlate with the aggressiveness of the glioma. 29,40 Previous studies have demonstrated that anti-ELTD1 treatments with pAb were effective in mouse GL261 and human G55 xenograft glioma models. 12 Other groups have also discovered that microRNA-139-5p directly binds onto and targets ELTD1 to inhibit cell proliferation in gliomas.…”

Section: Discussionmentioning

confidence: 99%

“…29 Therefore, we examined whether Notch levels changed with anti-ELTD1 treatment. 29 Therefore, we examined whether Notch levels changed with anti-ELTD1 treatment.…”

Section: Molecular-targeted Mris Of Representative Monoclonal An-mentioning

confidence: 99%

“…Notch signalling is important for cell differentiation, proliferation, as well as tumour angiogenesis, and normal vasculature has been shown to decrease ELTD1 expression. 29 Therefore, we examined whether Notch levels changed with anti-ELTD1 treatment. Positivity F I G U R E 4 mAb ELTD1 probe has significantly higher binding specificity against the tumour.…”

Section: Molecular-targeted Mris Of Representative Monoclonal An-mentioning

confidence: 99%

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Optimized monoclonal antibody treatment against ELTD1 for GBM in a G55 xenograft mouse model

Zalles

Smith

Ziegler

et al. 2019

J Cellular Molecular Medi

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Glioblastoma is an aggressive brain tumour found in adults, and the therapeutic approaches available have not significantly increased patient survival. Recently, we discovered that ELTD1, an angiogenic biomarker, is highly expressed in human gliomas. Polyclonal anti-ELTD1 treatments were effective in glioma pre-clinical models, however, pAb binding is potentially promiscuous. Therefore, the aim of this study was to determine the effects of an optimized monoclonal anti-ELTD1 treatment in G55 xenograft glioma models. MRI was used to assess the effects of the treatments on animal survival, tumour volumes, perfusion rates and binding specificity.Immunohistochemistry and histology were conducted to confirm and characterize microvessel density and Notch1 levels, and to locate the molecular probes. RNAsequencing was used to analyse the effects of the mAb treatment. Our monoclonal anti-ELTD1 treatment significantly increased animal survival, reduced tumour volumes, normalized the vasculature and showed higher binding specificity within the | 1739 ZALLES Et AL.

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“…The level of VEGF in HGG is greater than 10-fold compared with LGG [83]. Thus, drugs have been developed to interfere with angiogenesis by directly blocking ligand (VEGF) or receptor (VEGFR) or by targeting proangiogenic molecules that function by alternative mechanisms [84]. Of all targeted biological agents, only bevacizumab (Avastin) has demonstrated efficacy.…”

Section: Emergent Treatments Strategiesmentioning

confidence: 99%

Current Trends in Glioblastoma Treatment

Tătăranu¹,

Ciubotaru²,

Cazac³

et al. 2018

Brain Tumors - An Update

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Glioblastoma (also called glioblastoma multiforme-GBM) is a primary brain neoplasm, representing about 55% of all gliomas. It is a very aggressive and infiltrative tumor. Glioblastoma is usually highly malignant, with more than 90% 5-year mortality and a median survival of about 14.6 months. Compared to other cancers, the survival rate has not greatly changed over time and no current treatment is curative for this disease. Because the tumor has a heterogeneous cell population containing several types of cells, the treatment for GBM is one of the most challenging in clinical oncology. This chapter will discuss the current approaches in glioblastoma treatment, including resection techniques, chemotherapy and radiation therapy.

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Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1)viasiRNA-induced cell death in glioblastoma

Cited by 18 publications

References 25 publications

ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile

ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile

Optimized monoclonal antibody treatment against ELTD1 for GBM in a G55 xenograft mouse model

Current Trends in Glioblastoma Treatment

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