Li Timothy T, Alemayehu Mistre, Aziziyeh Adel I, Pape Cynthia, Pampillo Macarena, Postovit Lynne-Marie, Mills Gordon B, Babwah Andy V, Bhattacharya Moshmi
Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada.
Mol Cancer Res. 2009 Jul;7(7):1064-77. doi: 10.1158/1541-7786.MCR-08-0578.
The lipid mediator lysophosphatidic acid (LPA) plays a role in cancer progression and signals via specific G protein-coupled receptors, LPA(1-3). LPA has been shown to enhance the metastasis of breast carcinoma cells to bone. However, the mechanisms by which LPA receptors regulate breast cancer cell migration and invasion remain unclear. Breast cancer cell proliferation has been shown to be stimulated by Ral GTPases, a member of the Ras superfamily. Ral activity can be regulated by the multifunctional protein beta-arrestin. We now show that HS578T and MDA-MB-231 breast cancer cells and MDA-MB-435 melanoma cells have higher expression of beta-arrestin 1 mRNA compared with the nontumorigenic mammary MCF-10A cells. Moreover, we found that the mRNA levels of LPA1, LPA2, beta-arrestin 2, and Ral GTPases are elevated in the advanced stages of breast cancer. LPA stimulates the migration and invasion of MDA-MB-231 cells, but not of MCF-10A cells, and this is mediated by pertussis toxin-sensitive G proteins and LPA1. However, ectopic expression of LPA1 in MCF-10A cells caused these cells to acquire an invasive phenotype. Gene knockdown of either beta-arrestin or Ral proteins significantly impaired LPA-stimulated migration and invasion. Thus, our data show a novel role for beta-arrestin/Ral signaling in mediating LPA-induced breast cancer cell migration and invasion, two important processes in metastasis.
脂质介质溶血磷脂酸（LPA）在癌症进展中发挥作用，并通过特定的G蛋白偶联受体LPA(1 - 3)发出信号。已证明LPA可增强乳腺癌细胞向骨的转移。然而，LPA受体调节乳腺癌细胞迁移和侵袭的机制仍不清楚。已证明Ral GTPases（Ras超家族的成员）可刺激乳腺癌细胞增殖。Ral活性可由多功能蛋白β - 抑制蛋白调节。我们现在发现，与非致瘤性乳腺MCF - 10A细胞相比，HS578T和MDA - MB - 231乳腺癌细胞以及MDA - MB - 435黑色素瘤细胞中β - 抑制蛋白1 mRNA的表达更高。此外，我们发现LPA1、LPA2、β - 抑制蛋白2和Ral GTPases的mRNA水平在乳腺癌晚期升高。LPA刺激MDA - MB - 231细胞的迁移和侵袭，但不刺激MCF - 10A细胞，这是由百日咳毒素敏感的G蛋白和LPA1介导的。然而，MCF - 10A细胞中LPA1的异位表达使这些细胞获得了侵袭性表型。β - 抑制蛋白或Ral蛋白的基因敲低显著损害了LPA刺激的迁移和侵袭。因此，我们的数据显示了β - 抑制蛋白/Ral信号在介导LPA诱导的乳腺癌细胞迁移和侵袭中的新作用，这是转移过程中的两个重要过程。
