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

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 S1P 1 to inhibition through S1P 2 . LPA-induced cell migration was almost completely inhibited by either pertussis toxin, LPA 1 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 signalregulated 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 dominantnegative form of Cdc42. These findings suggest that, in glioma cells, the PI3K/Cdc42/p38MAPK and PI3K/ Rac1/JNK pathways are equally important for LPA 1 receptor-mediated migration.

Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness

“…As previously reported [19,25], S1P 2 stimulation led to decreased motility of glioma cells. In contrast, S1P stimulation of this receptor subtype caused an increased invasiveness of glioma cells through Matrigel.…”

Lysophosphatidic acid induces cell migration through the selective activation of Akt1

“…It has been reported that LPA activates many signaling pathways including the Ras/MEKK/MAPK, p38 MAPK, and JNK pathways (Bian et al, 2004;Malchinkhuu et al, 2005). It also has been reported that LPA stimulates DNA synthesis via activation of PI3K (Koh et al, 1998).…”

“…Occupation by LPA in its cognate receptors triggers activation of various signaling molecules during cell migration. For example, LPA activates the Ras/MEKK/MAPK pathway, p38 MAPK, and JNK (Bian et al, 2004;Malchinkhuu et al, 2005). It has been reported that PI3K is also activated by LPA stimulation through two different mechanisms.…”

Stimulatory Role of Lysophosphatidic Acid in Cyclooxygenase-2 Induction by Synovial Fluid of Patients with Rheumatoid Arthritis in Fibroblast-Like Synovial Cells

“…In addition to cytokines, the present study suggested a critical role of LPA in inflammatory responses in RA. Ki16425 has recently been shown to inhibit the migration and proliferation of cancer cells (18,(33)(34)(35) and smooth muscle cells (36) in vitro and of bone metastasis of ovarian and breast cancer cells in vivo (35). Thus, Ki16425 has been suggested to have potential as a therapeutic drug for cancer and vascular diseases.…”