endothelin-1 and Leukemia--Lymphocytic--Chronic--B-Cell

Endothelin-1 (ET-1) is a hormone peptide widely expressed and is involved in several biological processes, important not only for normal cell function but also for tumor development, including cell proliferation, invasion, metastasis, angiogenesis and osteogenesis. In accordance, ET-1 was already shown to contribute to the growth and progression of many different solid cancers. We recently demonstrated that ET-1 has a role in the pathogenesis of chronic lymphocytic leukemia (CLL) where it is abnormally expressed. In the context of this malignancy, ET-1 is able to mediate survival, drug-resistance and growth signals in leukemic cells. Previous studies, not conducted in CLL, have shown that ET-1 regulatory mechanisms are numerous and cell specific. Here, we valued the expression of ET-1 in CLL, in relation to DNA methylation but also in response to stimulation of some important pathways for the dialogue between CLL and microenvironment. We found that a high methylation of ET-1 first intron affects the basal expression of ET-1 in CLL. Moreover, we showed that the activation of CD40 or Toll-like receptor (TLR) by extracellular stimuli produces an augment of ET-1 level in CLL cells. Finally, we demonstrated the fundamental role of NF-kB signalling pathway in promoting and maintaining ET-1 expression in CLL cells, both in basal conditions and after CD40 activation.

Topics: Adult; Aged; Aged, 80 and over; CD40 Antigens; DNA Methylation; Endothelin-1; Epigenesis, Genetic; Female; Gene Expression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; NF-kappa B; Signal Transduction; Toll-Like Receptors; Tumor Cells, Cultured

The role of endothelium dysfunction in pathogenesis of B-cell mode of chronic lymphatic leukemia is still uncovered. However, detection of disorders of functional activity of vessel wall at early stages of development of this disease permits to widen actual diagnostic criteria of its initiation and thereafter to make more objective diagnostic itself. The study was targeted to establish the role of endothelium dysfunction in pathogenesis of initial stages (0-1 stages according classification Rai K. et al. 1975) of B-cell mode of chronic lymphatic leukemia. The article presents results of clinical laboratory examination of 30 patients with initial stages of B-cell mode of chronic lymphatic leukemia. The content of classic markers of endothelium dysfunction in blood serum were detected using one time solid-phase enzymoimmunoassay at the moment of admission to hospital before initiation of treatment. In patients with chronic lymphatic leukemia blood serum characterized by increasing of level of E-selectin. ICAM-1, endothelin-1, metabolites of nitrogen nitrite, angiotensin II. At the same time, content of protein C decreased at the stage 0-1 of mentioned pathology. Hence, it is recommended to apply determining in blood serum the content of markers of endothelium dysfunction as additional diagnostic criteria of development of paraneoplastic disorders at initial stages of chronic lymphatic leukemia. These markers include molecules of adhesion (E-selectin, ICAM-I), metabolites of nitrogen nitrite, endothelin-1, protein C. angiotensin II and homocysteine.

Topics: Aged; Aged, 80 and over; B-Lymphocytes; Endothelial Cells; Endothelin-1; Female; Humans; Intercellular Adhesion Molecule-1; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Endothelin A Receptor Antagonists; Endothelin-1; Gene Expression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis; Receptor, Endothelin A; Receptors, Antigen, B-Cell; Signal Transduction; Treatment Outcome