Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1
Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1
复制标题
DOI：
10.1074/jbc.m313927200
复制
发表时间：
2004-04-23
影响因子：
4.8
通讯作者：
Suzuki, R
中科院分区：
文献类型：
--
作者：
Hama, K;Aoki, J;Suzuki, R
自分泌运动因子（ATX）是一种肿瘤细胞运动刺激因子，最初从黑色素瘤细胞上清液中分离出来，参与调节癌细胞的侵袭性和转移性。最近，我们发现ATX与溶血磷脂酶D相同，后者将溶血磷脂酰胆碱转化为有效的生物活性磷脂介质溶血磷脂酸（LPA），这提高了ATX自分泌或旁分泌产生LPA有助于肿瘤细胞运动的可能性。在这里，我们证明了LPA和ATX通过LPA受体LPA介导细胞运动刺激活性（1）。在从lpa（1）（-/-）小鼠分离的成纤维细胞中，而不是从野生型或lpa（2）（-/-）小鼠分离的成纤维细胞中，完全不存在LPA和ATX刺激的细胞运动性。在lpa（1）（-/-）细胞中，LPA刺激的板状伪足形成显著减少，同时Rac 1活化减少。LPA刺激多种表达LPA 1的人癌细胞系的运动性，并且运动性被LPA（1）选择性拮抗剂Ki 16425减弱。本研究表明ATX和LPA（1）是肿瘤治疗的潜在靶点。
Autotaxin (ATX) is a tumor cell motility-stimulating factor originally isolated from melanoma cell supernatant that has been implicated in regulation of invasive and metastatic properties of cancer cells. Recently, we showed that ATX is identical to lysophospholipase D, which converts lysophosphatidylcholine to a potent bioactive phospholipid mediator, lysophosphatidic acid (LPA), raising the possibility that autocrine or paracrine production of LPA by ATX contributes to tumor cell motility. Here we demonstrate that LPA and ATX mediate cell motility-stimulating activity through the LPA receptor, LPA(1). In fibroblasts isolated from lpa(1)(-/-) mice, but not from wild-type or lpa(2)(-/-), cell motility stimulated with LPA and ATX was completely absent. In the lpa(1)(-/-) cells, LPA-stimulated lamellipodia formation was markedly diminished with a concomitant decrease in Rac1 activation. LPA stimulated the motility of multiple human cancer cell lines expressing LPA1, and the motility was attenuated by an LPA(1)-selective antagonist, Ki16425. The present study suggests that ATX and LPA(1) represent potential targets for cancer therapy.