Differential expression of endothelin converting enzyme 2 in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding endothelin converting enzyme 2, ECE2, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. ECE2 expression was significantly higher in high-grade serous ovarian tumors relative to normal fallopian tube. ECE2 expression correlated with overall survival in patients with ovarian cancer. These data indicate that expression of ECE2 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. ECE2 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones.

Effects of ECE-1b rs213045 and rs2038089 polymorphisms on the development of contrast-induced acute kidney injury in patients with acute coronary syndrome

Objective Endothelin-1 (ET-1) promotes the progression and induction of sclerotic renal changes in end-stage kidney disease. Membrane-bound endothelin-converting enzyme 1 (ECE-1) is involved in the production of ET-1. The aim of this study was to assess the effects of ECE-1b rs213045 and rs2038089 polymorphisms, which have been shown to be involved in the development of atherosclerosis, hypertension, and nephropathy, on the development of contrast-induced acute kidney injury (CI-AKI) in patients with acute coronary syndrome. Methods Our study included 38 patients with CI-AKI (CI-AKI[+]) and 55 patients without CI-AKI (CI-AKI[−]) who had coronary syndrome. The ECE-1b polymorphisms rs213045 and rs2038089 were assessed using real-time PCR. Serum ET-1 levels were measured by ELISA. Results The distributions of ECE-1b rs213045 and rs2038089 polymorphisms were similar between the two groups. Additionally, the serum ET-1 level did not different between the groups and was not associated with the ECE-1b polymorphisms. Peri-procedural low systolic blood pressure (SBP) was identified as a risk factor for CI-AKI development. Conclusion Our findings indicate that ECE-1b rs213045 and rs2038089 polymorphisms are not associated with CI-AKI development and that peri-procedural low SBP is a risk factor for CI-AKI. However, variations in ECE-1b rs2038089 may contribute to the development of CI-AKI.

Endothelin-converting enzyme-1 regulates glucagon-like peptide-1 receptor signalling and resensitisation

Following nutrient ingestion, glucagon-like peptide 1 (GLP-1) is secreted from intestinal L-cells and mediates anti-diabetic effects, most notably stimulating glucose-dependent insulin release from pancreatic β-cells but also inhibiting glucagon release, promoting satiety and weight reduction and potentially enhancing or preserving β-cell mass. These effects are mediated by the GLP-1 receptor (GLP-1R), which is a therapeutic target in type 2 diabetes. Although agonism at the GLP-1R has been well studied, desensitisation and resensitisation are perhaps less well explored. An understanding of these events is important, particularly in the design and use of novel receptor ligands. Here, using either HEK293 cells expressing the recombinant human GLP-1R or the pancreatic β-cell line, INS-1E with endogenous expressesion of the GLP-1R, we demonstrate GLP-1R desensitisation and subsequent resensitisation following removal of extracellular GLP-1 7-36 amide. Resensitisation is dependent on receptor internalisation, endosomal acidification and receptor recycling. Resensitisation is also regulated by endothelin-converting enzyme-1 (ECE-1) activity, most likely through proteolysis of GLP-1 in endosomes and the facilitation of GLP-1R dephosphorylation and recycling. Inhibition of ECE-1 activity also increases GLP-1-induced activation of extracellular signal-regulated kinase and generation of cAMP, suggesting processes dependent upon the lifetime of the internalised ligand–receptor complex.