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

2 Citations (Scopus)

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

Fingerprint

Oxygenases
Heme Oxygenase-1
p38 Mitogen-Activated Protein Kinases
Phospholipids
Lysophosphatidylcholines
Cell Movement
Down-Regulation
Mitogen-Activated Protein Kinase 1
Myeloid Cells
Cell Adhesion
Phosphorylation
Cell Proliferation
Lymphocytes
Cell Line
Injections
ceramide 1-phosphate
sphingosine 1-phosphate
lysophosphatidic acid
Neoplasms

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Cancer Research

Keywords

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

Cite this

Abdelbaset-Ismail, Ahmed ; Cymer, Monika ; Borkowska-Rzeszotek, Sylwia ; Brzeźniakiewicz-Janus, Katarzyna ; Rameshwar, Pranela ; Kakar, Sham S. ; Ratajczak, Janina ; Ratajczak, Mariusz Z. / 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. In: Stem Cell Reviews and Reports. 2019 ; Vol. 15, No. 1. pp. 139-154.
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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.",
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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. / Abdelbaset-Ismail, Ahmed; Cymer, Monika; Borkowska-Rzeszotek, Sylwia; Brzeźniakiewicz-Janus, Katarzyna; Rameshwar, Pranela; Kakar, Sham S.; Ratajczak, Janina; Ratajczak, Mariusz Z.

In: Stem Cell Reviews and Reports, Vol. 15, No. 1, 15.02.2019, p. 139-154.

Research output: Contribution to journalReview article

TY - JOUR

T1 - 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

AU - Abdelbaset-Ismail, Ahmed

AU - Cymer, Monika

AU - Borkowska-Rzeszotek, Sylwia

AU - Brzeźniakiewicz-Janus, Katarzyna

AU - Rameshwar, Pranela

AU - Kakar, Sham S.

AU - Ratajczak, Janina

AU - Ratajczak, Mariusz Z.

PY - 2019/2/15

Y1 - 2019/2/15

N2 - 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.

AB - 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.

KW - C1P

KW - HO-1

KW - HO-1 activators

KW - LPA

KW - LPC

KW - Leukemia

KW - S1P

KW - p38 MAPK

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U2 - 10.1007/s12015-018-9853-6

DO - 10.1007/s12015-018-9853-6

M3 - Review article

C2 - 30302660

AN - SCOPUS:85055052019

VL - 15

SP - 139

EP - 154

JO - Stem Cell Reviews

JF - Stem Cell Reviews

SN - 1550-8943

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