title: Endothelin-1 promotes survival and chemoresistance in chronic lymphocytic leukemia B cells through ETA receptor.
abstract: The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ET(A)R and ETBR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ET(A)R axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ETA 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(A)R triggering. Moreover, the blockade of ET(A)R 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(A)R 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(A)R 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(A)R signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ET(A)R inhibition.
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Maffei
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Bulgarelli
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiorcari
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinelli
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Castelli
authors.affiliation: Hematology Division, Piacenza Hospital, Piacenza, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Valenti
authors.affiliation: Hematology Division, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Goretta
authors.initials: G
authors.lastname: Bonacorsi
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Zucchini
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Potenza
authors.affiliation: Hematology Division, Piacenza Hospital, Piacenza, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Vallisa
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.affiliation: Hematology Division, S.Eugenio Hospital and University of Tor Vergata, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
authors.affiliation: Cancer Sciences Unit, CRUK Clinical Centre, University of Southampton, Southampton, United Kingdom; Hematology Division, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Hematology Division, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Narni
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.affiliation: Hematology Division, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D011947:Receptors, Antigen, B-Cell