Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation

• Published in: PloS one 2016-01, Vol.11 (1), p.e0148137-e0148137
• Main Authors: Messias, Carolina V, Santana-Van-Vliet, Eliane, Lemos, Julia P, Moreira, Otacilio C, Cotta-de-Almeida, Vinicius, Savino, Wilson, Mendes-da-Cruz, Daniella Arêas
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; AKT protein; Analysis; Anilides - pharmacology; Biology; Biology and Life Sciences; Blockage; Cancer; Cell adhesion & migration; Cell differentiation; Cell growth; Cell Line, Tumor; Chemotaxis; Chemotaxis - drug effects; G protein-coupled receptors; Gene expression; Gene Expression Regulation, Leukemic; Genetic aspects; Humans; Kinases; Laboratories; Leukemia; Leukocyte migration; Lipids; Lymphocytes; Lymphocytes T; Lymphoma; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; Medicine and Health Sciences; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Molting; Motility; mRNA; Organophosphonates - pharmacology; Organs; Phosphates; Phosphorylation; Phosphorylation - drug effects; Physical Sciences; Physiological aspects; Prostate; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Receptors; Receptors, Lysosphingolipid - genetics; Receptors, Lysosphingolipid - metabolism; Research and Analysis Methods; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Signaling; Sphingosine; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine - pharmacology; Sphingosine 1-phosphate; T cells; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Thymus
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0148137

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in several physiological processes including cell migration and differentiation. S1P signaling is mediated through five G protein-coupled receptors (S1P1-S1P5). S1P1 is crucial to the exit of T-lymphocytes from the thymus and peripheral lymphoid organs through a gradient of S1P. We have previously observed that T-ALL and T-LBL blasts express S1P1. Herein we analyzed the role of S1P receptors in the migratory pattern of human T-cell neoplastic blasts. S1P-triggered cell migration was directly related to S1P1 expression. T-ALL blasts expressing low levels of S1P1 mRNA (HPB-ALL) did not migrate toward S1P, whereas those expressing higher levels of S1P1 (MOLT-4, JURKAT and CEM) did migrate. The S1P ligand induced T-ALL cells chemotaxis in concentrations up to 500 nM and induced fugetaxis in higher concentrations (1000-10000 nM) through interactions with S1P1. When S1P1 was specifically blocked by the W146 compound, S1P-induced migration at lower concentrations was reduced, whereas higher concentrations induced cell migration. Furthermore, we observed that S1P/S1P1 interactions induced ERK and AKT phosphorylation, and modulation of Rac1 activity. Responding T-ALL blasts also expressed S1P3 mRNA but blockage of this receptor did not modify migratory responses. Our results indicate that S1P is involved in the migration of T-ALL/LBL blasts, which is dependent on S1P1 expression. Moreover, S1P concentrations in the given microenvironment might induce dose-dependent chemotaxis or fugetaxis of T-ALL blasts.