Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells
Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells
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DOI：
10.1038/sj.onc.1208805
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发表时间：
2005-10-06
期刊：
影响因子：
8
通讯作者：
Okajima, F
中科院分区：
文献类型：
--
作者：
Malchinkhuu, E;Sato, K;Okajima, F
1-油酰基-sn-甘油-3-磷酸或溶血磷脂酸（LPA）和鞘氨醇-1-磷酸（S1 P）在恶性疾病的调节中的潜在作用已被广泛考虑。在这项研究中，我们发现在转化的星形胶质细胞中，表达pro。LPA和S1 P对细胞运动的作用方式发生了变化：LPA刺激细胞迁移能力的获得发生了变化，S1 P对细胞迁移的反应由S1 P的刺激（1）变为S1 P的抑制（2）。百日咳毒素、LPA（1）受体拮抗剂Ki 16425（3（4[4（[1（2氯苯基）乙氧基]羰基氨基）-3-甲基-5-异恶唑基]苄基磺酰基）丙酸）或磷脂酰肌醇3-激酶（PI 3 K）抑制剂渥曼青霉素几乎完全抑制LPA诱导的细胞迁移。LPA诱导的作用也被抑制，但不完全，由几个特定的抑制剂的细胞内信号通路，包括Rac 1，Cdc 42，p38丝裂原活化蛋白激酶（p38 MAPK）和c-Jun末端激酶（JNK），但不是细胞外信号调节激酶。然而，几乎完全抑制对LPA的迁移反应，需要同时抑制p38 MAPK和JNK途径。Rac 1的抑制抑制JNK，但不是p38 MAPK，而p38 MAPK的活性被取消的显性负性形式的Cdc 42。这些发现表明，在胶质瘤细胞中，PI 3 K/Cdc 42/p38 MAPK和PI 3 K/Rac 1/JNK通路对LPA 1受体介导的迁移同样重要。
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 pro. le 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(2chlorophenyl)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.