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Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells

Oncogene volume 24, pages 6676–6688 (2005)Cite this article

Abstract

A potential role for 1-oleoyl-sn-glycero-3-phosphate or lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) in the regulation of malignant diseases has been widely considered. In this study, we found that in transformed astroglial cells, the expression profile of lysophospholipid receptor mRNA and the action modes of LPA and S1P on cell motility were changed: there was a change in the acquisition of the ability of LPA to stimulate cell migration and a change in the migratory response to S1P from stimulation through S1P1 to inhibition through S1P2. LPA-induced cell migration was almost completely inhibited by either pertussis toxin, LPA1 receptor antagonists including Ki16425 (3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfonyl)propanoic acid) or an inhibitor of phosphatidylinositol 3-kinase (PI3K) wortmannin. The LPA-induced action was also suppressed, although incompletely, by several specific inhibitors for intracellular signaling pathways including Rac1, Cdc42, p38 mitogen-activated protein kinase (p38MAPK) and c-Jun terminal kinase (JNK), but not extracellular signal-regulated kinase. Nearly complete inhibition of migration response to LPA, however, required simultaneous inhibition of both the p38MAPK and JNK pathways. Inhibition of Rac1 suppressed JNK but not p38MAPK, while the activity of p38MAPK was abolished by a dominant-negative form of Cdc42. These findings suggest that, in glioma cells, the PI3K/Cdc42/p38MAPK and PI3K/Rac1/JNK pathways are equally important for LPA1 receptor-mediated migration.

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Abbreviations

LPA:

1-oleoyl-sn-glycero-3-phosphate or lysophosphatidic acid

S1P:

sphingosine-1-phosphate

PI3K:

phosphatidylinositol 3-kinase

MAP kinase:

mitogen-activated protein kinase

p38MAPK:

p38MAP kinase

p38-DN:

dominant-negative mutant for p38MAPK

JNK:

c-Jun terminal kinase

JIP1-JBD:

JNK-binding domain of JNK-interacting protein-1

ERK:

extracellular signal-regulated kinase

MEK:

ERK kinase

T17NRac1:

dominant-negative mutant for Rac1

T17NCdc42:

dominant-negative mutant for Cdc42

PDGF:

platelet-derived growth factor

EGF:

epidermal growth factor

DGPP 8:0:

dioctylglycerol pyrophosphate

G-protein:

GTP-binding regulatory protein

PTX:

pertussis toxin

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

GFP:

green fluorescent protein

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Acknowledgements

We are grateful to Professor Kevin R Lynch of University of Virginia School of Medicine and Dr Hideo Ohta of Kirin Brewery Co, Ltd for generous gift of VPC12249 and Ki16425, respectively. We thank Professor Yoh Takuwa of Kanazawa University Graduate School of Medicine for generous gift of human S1P2 cDNA. We also thank Ms Chisuko Uchiyama, Ms Mayumi Komachi and Mr Masayuki Tobo for technical assistance. This work was supported by a Grant-in-Aid for scientific research from the Japan Society for the Promotion of Science, a grant of the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan and grants from ONO Medical Research Foundation, The Nakatomi Foundation and Uehara Memorial Foundation.

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Authors and Affiliations

  1. Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15, Showa-machi, 371-8512, Maebashi, Japan

    Enkhzol Malchinkhuu, Koichi Sato, Yuta Horiuchi, Chihiro Mogi, Hideaki Tomura & Fumikazu Okajima

  2. Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan

    Susumu Ohwada

  3. Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan

    Shogo Ishiuchi & Nobuhito Saito

  4. Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Hitoshi Kurose

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Malchinkhuu, E., Sato, K., Horiuchi, Y. et al. Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells. Oncogene 24, 6676–6688 (2005). https://doi.org/10.1038/sj.onc.1208805

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