Abstract
The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ETAR and ETBR), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ETAR 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 ETAR triggering. Moreover, the blockade of ETAR by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ETAR 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. ETAR 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/ETAR signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ETAR inhibition.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western countries
Comparing the expression levels between purified CLL cells (n = 10) and normal B cells (n = 6) collected from peripheral blood, we found that ET-1 and ETAR were significantly over-expressed in CLL cells (Figure 1A)
ET-1 was discovered as a potent vasoconstrictor, but later it was demonstrated to possess a wide range of pleiotropic functions, including cell survival, proliferation, angiogenesis, and regulation of tumor-infiltrating immune cells, invasion and metastasis [12,18]
Summary
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western countries. The small proportion of proliferating CLL cells is thought to replenish leukemic population inside specific structures known as proliferation centers, which are localized in lymph nodes and bone marrow. CLL cells experience a chronic antigen contact that implies the engagement of the B cell receptor (BCR) signaling, leading to activation of downstream pro-survival signaling molecules such as nuclear factor-kB, Raf, mitogen-activated protein kinase MEK and extracellular signal regulated kinase (ERK) [4]. CLL contact with endothelial cells mediates survival, proliferation and drug-resistance [6,8,9,10]. Among the most up-regulated genes activated in CLL cells after contact with endothelial cells, we recently reported Endothelin-1 (ET-1) with a 9-fold increase [8]
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