Abstract
Bioactive phospholipids, including sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), lysophosphatidylcholine (LPC), and its derivative lysophosphatidic acid (LPA), have emerged as important mediators regulating the trafficking of normal and cancer cells. While the role of S1P in regulating migration of hematopoietic cells is well established, in this work we compared its biological effects to the effects of C1P, LPC, and LPA. We employed 10 human myeloid and lymphoid cell lines as well as blasts from AML patients. We observed that human leukemic cells express functional receptors for phospholipids and respond to stimulation by phosphorylation of p42/44 MAPK and AKT. We also found that bioactive phospholipids enhanced cell migration and adhesion of leukemic cells by downregulating expression of HO-1 and iNOS in a p38 MAPK-dependent manner but did not affect cell proliferation. By contrast, downregulation of p38 MAPK by SB203580 enhanced expression of HO-1 and iNOS and decreased migration of leukemic cells in vitro and their seeding efficiency to vital organs in vivo after injection into immunodeficient mice. Based on these findings, we demonstrate that, besides S1P, human leukemic cells also respond to C1P, LPC, and LPA. Since the prometastatic effects of bioactive phospholipids in vivo were mediated, at least in part, by downregulating HO-1 and iNOS expression in a p38 MAPK-dependent manner, we propose that inhibitors of p38 MAPK or stimulators of HO-1 activity will find application in inhibiting the spread of leukemic cells in response to bioactive phospholipids.
Highlights
Evidence has accumulated that, in addition to well-known peptide-based factors, including growth factors, cytokines, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland 4 Department of Physiology, Pomeranian Medical University, Szczecin, Poland 5 Department of Hematology, Multi-specialist Hospital, University of Zielona Gora, Gorzow Wlkp, Poland 6 Rutgers New Jersey Medical School, Newark, NJ, USA and chemokines, bioactive phospholipids modulate the migration of normal and malignant cells [1,2,3,4,5,6,7]
While S1P has been reported to be involved in the pathogenesis of CML, Acute Myeloid Leukemia (AML), ALL, and multiple myeloma and to chemoattract leukemic cell lines [12,13,14,15], the effects of a second bioactive phosphosphingolipid, C1P, on leukemic cells [16] have so far been understudied
Human Leukemia Cell Lines Express Receptors for Bioactive Phospholipids and Respond to Stimulation by Enhanced Motility and Adhesion but Not Proliferation To demonstrate that the leukemic cells employed in our studies express receptors for S1P, lysophosphatidic acid (LPA), and LPC, we evaluated the expression of these receptors at the mRNA level (Fig. 1) and found that several are expressed in human leukemic cell lines
Summary
In addition to well-known peptide-based factors, including growth factors, cytokines, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland 4 Department of Physiology, Pomeranian Medical University, Szczecin, Poland 5 Department of Hematology, Multi-specialist Hospital, University of Zielona Gora, Gorzow Wlkp, Poland 6 Rutgers New Jersey Medical School, Newark, NJ, USA and chemokines, bioactive phospholipids modulate the migration of normal and malignant cells [1,2,3,4,5,6,7] These lipid-based molecules are already present at biologically relevant concentrations in tissues and blood plasma, and their levels increase in several situations related to organ/tissue damage. With the exception of C1P, the receptors for these phospholipids have been cloned
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