Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1*
Lysophosphatidic Acid (LPA) in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells through LPA1*
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DOI：
10.1074/jbc.m308133200
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发表时间：
2004-02
影响因子：
4.8
通讯作者：
Takayuki Yamada;Koichi Sato;Mayumi Komachi;Enkhzol Malchinkhuu;M. Tobo;Takao Kimura;A. Kuwabara;Y. Yanagita;Toshirou Ikeya;Y. Tanahashi;T. Ogawa;S. Ohwada;Y. Morishita;H. Ohta;D. Im;K. Tamoto;H. Tomura;F. Okajima
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文献类型：
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作者：
Takayuki Yamada;Koichi Sato;Mayumi Komachi;Enkhzol Malchinkhuu;M. Tobo;Takao Kimura;A. Kuwabara;Y. Yanagita;Toshirou Ikeya;Y. Tanahashi;T. Ogawa;S. Ohwada;Y. Morishita;H. Ohta;D. Im;K. Tamoto;H. Tomura;F. Okajima
恶性腹水中的细胞因子和生长因子被认为调节癌细胞和正常宿主细胞的多种细胞活性。癌细胞的运动性对于侵袭和转移是特别重要的活动。在这里，我们检查了患者和癌细胞注射小鼠腹水中负责细胞运动的成分。腹水可显著促进胰腺癌细胞的迁移。这种反应被百日咳毒素、单甘酯脂肪酶（一种水解溶血磷脂酸（LPA）的酶）以及LPA受体（LPA 1和LPA 3）的拮抗剂Ki 16425和VPC 12249抑制或消除，但不被LPA 3选择性拮抗剂抑制或消除。这些药物也抑制对LPA的反应，但不抑制对表皮生长因子的反应。在恶性腹水中，LPA以高水平存在，这可以解释迁移活性，并且通过脂质提取和随后的薄层色谱法对腹水的分级研究表明LPA为活性组分。LPA1受体mRNA在具有高迁移活性的胰腺癌细胞中表达显著水平，但在具有低迁移活性的细胞中不表达。针对LPA 1受体的小干扰RNA特异性地抑制受体mRNA的表达，并消除对腹水的迁移反应。这些结果表明，LPA是胰腺癌细胞运动的腹水的关键组分，LPA 1受体可能介导这种活性。LPA受体拮抗剂Ki16425是潜在的抗肿瘤细胞迁移和侵袭的药物。
Cytokines and growth factors in malignant ascites are thought to modulate a variety of cellular activities of cancer cells and normal host cells. The motility of cancer cells is an especially important activity for invasion and metastasis. Here, we examined the components in ascites, which are responsible for cell motility, from patients and cancer cell-injected mice. Ascites remarkably stimulated the migration of pancreatic cancer cells. This response was inhibited or abolished by pertussis toxin, monoglyceride lipase, an enzyme hydrolyzing lysophosphatidic acid (LPA), and Ki16425 and VPC12249, antagonists for LPA receptors (LPA1 and LPA3), but not by an LPA3-selective antagonist. These agents also inhibited the response to LPA but not to the epidermal growth factor. In malignant ascites, LPA is present at a high level, which can explain the migration activity, and the fractionation study of ascites by lipid extraction and subsequent thin-layer chromatography indicated LPA as an active component. A significant level of LPA1 receptor mRNA is expressed in pancreatic cancer cells with high migration activity to ascites but not in cells with low migration activity. Small interfering RNA against LPA1 receptors specifically inhibited the receptor mRNA expression and abolished the migration response to ascites. These results suggest that LPA is a critical component of ascites for the motility of pancreatic cancer cells and LPA1 receptors may mediate this activity. LPA receptor antagonists including Ki16425 are potential therapeutic drugs against the migration and invasion of cancer cells.