Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through et_a receptor

The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ET_AR and ET_BR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ET_AR axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ET_A receptor as compared to normal B cells. ET-1 peptide stimulated phosphoinositide-3-kinase and mitogen-activated protein kinase signaling pathways, improved survival and promoted proliferation of leukemic cells throughout ET_AR triggering. Moreover, the blockade of ET_AR by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ET_AR via BQ-123 interferes with ERK phosphorylation and CLL pro-survival effect mediated by B-cell receptor (BCR) activation. The pro-apoptotic effect of phosphoinositide-3-kinase δ inhibitor idelalisib and mitogen-activated protein kinase inhibitor PD98059 was decreased by the addition of ET-1 peptide. Then, ET-1 also reduced the cytotoxic effect of fludarabine on CLL cells cultured alone or co-cultured on endothelial layers. ET_AR blockade by BQ-123 inhibited the ET-1-mediated protection against drug-induced apoptosis. Lastly, higher plasma levels of big ET-1 were detected in patients (n = 151) with unfavourable prognostic factors and shorter time to first treatment. In conclusion, our data describe for the first time a role of ET-1/ET_AR signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ET_AR inhibition.