Hasegawa Yutaka, Murph Mandi, Yu Shuangxing, Tigyi Gabor, Mills Gordon B
Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, 7435 Fannin Street, Houston, TX 77054, USA.
Mol Oncol. 2008 Jun;2(1):54-69. doi: 10.1016/j.molonc.2008.03.009.
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 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.
前列腺癌仍然是美国男性中最常被诊断出的恶性肿瘤，也是癌症死亡的第二大主要原因。激素难治性转移性疾病迄今为止尚无分子疗法，生存率很低。溶血磷脂酸（LPA）是一种生物活性脂质，在多种癌细胞谱系中表现出运动、侵袭、生长、增殖和存活作用。细胞表达LPA特异性G蛋白偶联受体LPA(1)、LPA(2)、LPA(3)和LPA(4)以及其他LPA受体的不同组合，这些受体与LPA结合从而调节脂质信号传导。特定LPA受体在前列腺癌溶血脂信号传导功能结果中的作用仍有待充分阐明。我们假设LPA可以通过激活参与运动的肌动蛋白相关蛋白，包括血管舒张刺激磷蛋白（VASP），通过特定的LPA受体引发细胞迁移。在本研究中，我们证明LPA诱导的细胞板状伪足形成依赖于LPA受体介导的VASP磷酸化，这表明LPA存在以前未知的调节作用。LPA通过蛋白激酶A（PKA）诱导VASP在Ser(157)位点磷酸化，因为PKA抑制可消除这种刺激。此外，我们发现敲低VASP或LPA受体表达可降低LPA诱导的板状伪足形成和迁移的作用，这表明LPA受体诱导的VASP磷酸化是迁移起始的关键介质。因此，除先前涉及的LPA(1)受体外，LPA(2)和LPA(3)受体在细胞运动中发挥作用，可能促进侵袭和转移。针对LPA途径的新兴药物可能对前列腺癌转移进展的治疗有益。
