Bioactive Phospholipids Enhance Migration and Adhesion of Human Leukemic Cells by Inhibiting Heme Oxygenase 1 (HO-1) and Inducible Nitric Oxygenase Synthase (iNOS) in a p38 MAPK-Dependent Manner

Ahmed Abdelbaset-Ismail, Monika Cymer, Sylwia Borkowska-Rzeszotek, Katarzyna Brzeźniakiewicz-Janus, Pranela Rameshwar, Sham S. Kakar, Janina Ratajczak, Mariusz Z. Ratajczak

Research output: Contribution to journalReview article

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)139-154
Number of pages16
JournalStem Cell Reviews and Reports
Volume15
Issue number1
DOIs
StatePublished - Feb 15 2019

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Cancer Research

Keywords

  • C1P
  • HO-1
  • HO-1 activators
  • LPA
  • LPC
  • Leukemia
  • S1P
  • p38 MAPK

Fingerprint Dive into the research topics of 'Bioactive Phospholipids Enhance Migration and Adhesion of Human Leukemic Cells by Inhibiting Heme Oxygenase 1 (HO-1) and Inducible Nitric Oxygenase Synthase (iNOS) in a p38 MAPK-Dependent Manner'. Together they form a unique fingerprint.

  • Cite this