Role of Rap1B and Tumor Suppressor PTEN in the Negative Regulation of Lysophosphatidic Acid-induced Migration by Isoproterenol in Glioma Cells
Role of Rap1B and Tumor Suppressor PTEN in the Negative Regulation of Lysophosphatidic Acid-induced Migration by Isoproterenol in Glioma Cells
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DOI：
10.1091/mbc.e09-08-0692
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发表时间：
2009-12-15
影响因子：
3.3
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
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作者：
Malchinkhuu, Enkhzol;Sato, Koichi;Okajima, Fumikazu
阐明负向调节人类神经胶质瘤细胞侵袭行为的机制对于寻找新的治疗方法具有重要意义。在这项研究中，我们重点关注溶血磷脂酸（LPA）诱导的神经胶质瘤细胞迁移的负调节。除了药理学工具外，我们还使用小干扰 RNA 和显性失活基因策略，发现异丙肾上腺素 (ISO) 和 1-磷酸鞘氨醇 (S1P) 对 LPA 诱导的迁移具有负面但不同的调节作用。 ISO 诱导的神经胶质瘤细胞迁移抑制是通过 β(2)-肾上腺素受体/cAMP/Epac/Rap1B/Rac 抑制来实现的，而 S1P 已被证明可以通过 S1P(2) 受体/Rho 介导的 Rac1 下调来抑制细胞迁移。 10 号染色体上缺失的肿瘤抑制磷酸酶和张力蛋白同源物 (PTEN) 的表达是 ISO 诱导和 Rap1B 介导的对 LPA 响应的迁移、Rac1 激活和 Akt 激活的抑制作用所必需的。因此，PTEN 介导的磷脂酰肌醇 3 激酶活性下调可能参与了 Rap1B 依赖性 Rac1 活性抑制的调节。这些发现表明，至少有两种不同的抑制途径，由 S1P(2) 受体和 β(2)-肾上腺素能受体介导，来控制神经胶质瘤细胞的迁移行为，从而控制胶质瘤细胞的侵袭行为。
The clarification of mechanisms that negatively regulate the invasive behavior of human glioma cells is of great importance in order to find new methods of treatment. In this study, we have focused on the negative regulation of lysophosphatidic acid (LPA)-induced migration in glioma cells. Using small interference RNA and dominant-negative gene strategies in addition to pharmacological tools, we found that isoproterenol (ISO) and sphingosine-1-phosphate (S1P) negatively but differently regulate the LPA-induced migration. ISO-induced suppression of the migration of glioma cells occurs via beta(2)-adrenergic receptor/cAMP/Epac/Rap1B/inhibition of Rac, whereas S1P has been shown to suppress the migration of the cells through S1P(2) receptor/ Rho-mediated down-regulation of Rac1. The expression of tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is required for the inhibitory ISO-induced and Rap1B-mediated actions on the migration, Rac1 activation, and Akt activation in response to LPA. Thus, the PTEN-mediated down-regulation of phosphatidylinositol 3-kinase activity may be involved in the regulation of Rap1B-dependent inhibition of Rac1 activity. These findings suggest that there are at least two distinct inhibitory pathways, which are mediated by the S1P(2) receptor and beta(2)-adrenergic receptor, to control the migratory, hence invasive, behavior of glioma cells.