Crosstalk between BCR-ABL and protease-activated receptor 1 (PAR1) suggests a novel target in chronic myeloid leukemia

•Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is overexpressed in the blast crisis of chronic myeloid leukemia (CML).•CML cell lines transfected with the BCR-ABL1 oncogene show increased PAR1 expression.•Inhibition of PAR1 reduces BCR-ABL1 and vascular endothelial growth...

Full description

Saved in:

Bibliographic Details
Published in:	Experimental hematology Vol. 66; pp. 50 - 62
Main Authors:	Borges, Camilla de S., Ferreira, Aline F., Almeida, Vitor H., Gomes, Fausto G., Berzoti-Coelho, Maria Gabriela, Cacemiro, Maira da Costa, Nunes, Natalia S., Figueiredo-Pontes, Lorena L., Simões, Belinda P., Castro, Fabíola A., Monteiro, Robson Q.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 01-10-2018
Subjects:	Adult Aged Antineoplastic Agents - pharmacology Apoptosis - drug effects Case-Control Studies Cell Line, Tumor Chromones - pharmacology Disease Progression Dose-Response Relationship, Drug Female Flavonoids - pharmacology Fusion Proteins, bcr-abl - genetics Fusion Proteins, bcr-abl - metabolism Gene Expression Regulation, Leukemic Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology Male Middle Aged Morpholines - pharmacology Myeloid Cells - drug effects Myeloid Cells - metabolism Myeloid Cells - pathology Philadelphia Chromosome Protein Kinase Inhibitors - pharmacology Pyrimidines - pharmacology Pyrroles - pharmacology Quinazolines - pharmacology Receptor, PAR-1 - genetics Receptor, PAR-1 - metabolism Signal Transduction Treatment Outcome Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	•Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is overexpressed in the blast crisis of chronic myeloid leukemia (CML).•CML cell lines transfected with the BCR-ABL1 oncogene show increased PAR1 expression.•Inhibition of PAR1 reduces BCR-ABL1 and vascular endothelial growth factor (VEGF) expression in CML cell lines.•A decreased PAR1 expression is observed in tyrosine kinase inhibitor (TKI)-responsive CML patients.•TKI-resistant CML patients exhibit increased PAR1 levels. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which generates the oncogene BCR-ABL1. Protease-activated receptor 1 (PAR1) is involved in tumor progression and angiogenesis. We have previously reported that PAR1 expression is elevated in human leukemias that display a more aggressive clinical behavior, including the blast crisis of CML. In this study, we analyzed the crosstalk between the oncoprotein BCR-ABL and PAR1 in CML. Leukemic cell lines transfected with the BCR-ABL1 oncogene showed significantly higher expression levels of PAR1 compared with that of wild-type counterparts. This phenomenon was reversed by treatment with tyrosine kinase inhibitors (TKIs). Conversely, treatment with the PAR1 antagonist SCH79797 inhibited BCR-ABL expression. The PAR1 antagonist induced apoptosis in a dose- and time-dependent manner. Higher vascular endothelial growth factor (VEGF) levels were observed in cells transfected with BCR-ABL1 than in their wild-type counterparts. VEGF expression was strongly inhibited after treatment with either TKIs or the PAR1 antagonist. Finally, we evaluated PAR1 expression in CML patients who were either in the blast or chronic phases and had either received TKI treatment or no treatment. A significant decrease in PAR1 expression was observed in treatment-responsive patients, as opposed to a significant increase in PAR1 expression levels in treatment-resistant patients. Patients classified as high risk according to the Sokal index showed higher PAR1 expression levels. Our results demonstrate the crosstalk between BCR-ABL and PAR1. These data may offer important insight into the development of new therapeutic strategies for CML.
ISSN:	0301-472X 1873-2399
DOI:	10.1016/j.exphem.2018.07.008