Lysophosphatidic acid (LPA)-induced vasodidator-stimulated phosphoprotein mediates lamellipodia formation to initiate motility in PC-3 prostate cancer cells
Lysophosphatidic acid (LPA)-induced vasodidator-stimulated phosphoprotein mediates lamellipodia formation to initiate motility in PC-3 prostate cancer cells
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DOI：
10.1016/j.molonc.2008.03.009
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发表时间：
2008-06-01
影响因子：
6.6
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Hasegawa, Yutaka;Murph, Mandi;Mills, Gordon B.
前列腺癌仍然是美国男性中最常诊断的恶性肿瘤，也是癌症死亡的第二大原因。激素难治性、转移性疾病至今没有分子疗法，生存率很低。溶血磷脂酸（LPA）是一种生物活性脂质，在多种癌细胞系中表现出运动性、侵袭性、生长、增殖和存活作用。细胞表达LPA特异性G蛋白偶联受体的不同组合，LPA（1）、LPA（2）、LPA（3）和LPA（4）以及其他LPA受体，其结合LPA并从而调节脂质信号传导。在前列腺癌中，特异性LPA受体在溶血脂质信号传导的功能结果中的作用仍有待充分阐明。我们假设，LPA可以启动细胞迁移，通过特定的LPA受体激活肌动蛋白相关蛋白参与运动，包括血管舒张刺激磷蛋白（VASP）。在本研究中，我们证明了LPA诱导的细胞中片状伪足的形成依赖于LPA受体介导的VASP磷酸化，这表明了LPA以前未知的调节。LPA通过蛋白激酶A（PKA）诱导VASP在Ser（157）处的磷酸化，因为PKA抑制消除了刺激。此外，我们发现，LPA诱导的片状伪足形成和迁移的影响，降低VASP或LPA受体的表达，这表明LPA受体诱导的VASP磷酸化是一个关键的介质迁移启动。因此，LPA（2）和LPA（3）受体，除了先前涉及的LPA（1）受体之外，在细胞运动中发挥作用，可能有助于侵袭和转移。针对LPA途径的新兴药物可能有助于治疗前列腺癌的转移性进展。(C)2008年欧洲生物化学学会联合会。Elsevier B.V.出版，保留所有权利。
Prostate cancer remains the most frequently diagnosed malignancy and the second leading cause of cancer mortality among men in the United States. Hormone refractory, metastatic disease has no molecular therapeutics to date and survival is poor. Lysophosphatidic acid (LPA) is a bioactive lipid exhibiting motility, invasive, growth, proliferative and survival effects in multiple cancer cell lineages. Cells express different combinations of LPA-specific G protein-coupled receptors, LPA(1), LPA(2) LPA(3), and LPA(4) as well as other LPA receptors, which bind LPA and thereby regulate lipid signaling. The role of specific LPA receptors in functional outcomes of lysolipid signaling remains to be fully elucidated in prostate cancer. We hypothesized that LPA can initiate cell migration through specific LPA receptors by activating actin-associating proteins involved in motility, including the vasodilator-stimulated phosphoprotein (VASP). In the present study, we demonstrate that LPA-induced lamellipodia formation in cells is dependent on LPA receptor-mediated phosphorylation of VASP, demonstrating a previously unknown regulation by LPA. LPA induces phosphorylation of VASP at Ser(157), through protein kinase A (PKA) since the stimulation was abrogated by PKA inhibition. In addition, we found that the effects of LPA-induced lamellipodia formation and migration were reduced by knockdown of either VASP or LPA receptor expression, suggesting that LPA receptor-induced VASP phosphorylation is a critical mediator of migration initiation. Thus the LPA(2) and LPA(3) receptors, in addition to the previously implicated LPA(1) receptor, play a role in cellular motility potentially contributing to invasion and metastases. Emerging drugs targeting the LPA pathway may be beneficial for the treatment of metastatic progression in prostate cancer. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.