Statins inhibit T-acute lymphoblastic leukemia cell adhesion and migration through Rap1b
Statins inhibit T-acute lymphoblastic leukemia cell adhesion and migration through Rap1b
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DOI：
10.1189/jlb.0810441
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发表时间：
2011-04-01
影响因子：
5.5
通讯作者：
Ridley, Anne J.
中科院分区：
文献类型：
--
作者：
Infante, Elvira;Heasman, Sarah J.;Ridley, Anne J.
已知他汀类药物抑制Ras超家族GTP酶的信号传导并减少T细胞与ICAM-1的粘附。在这里，我们解决的假设，他汀类药物影响T细胞的粘附和迁移，通过调节特定的GTP酶的功能。他汀类药物抑制甲羟戊酸的合成，甲羟戊酸是法呢基和香叶基香叶基类异戊二烯合成所必需的。Ras超家族GTP酶是后异戊二烯化的，以促进其锚定到膜，在那里它们起到刺激信号转导过程的作用。我们证明，1 μ M他汀类药物抑制T-ALL细胞系CCRF-CEM和CCRF-CEM和PEER T-ALL细胞的TEM的粘附、迁移和趋化性，但需要更高的他汀类药物浓度来抑制原代T细胞的粘附。在用GGTI-298或RNA干扰介导的Rap1b敲低治疗后观察到类似的效果，但不包括Rap1a、Rac1、Rac2、RhoA或Cdc42。他汀类药物还改变Rap1活性和Rap1b定位。Rap1在原代T细胞中的水平高于T-ALL细胞，这可以解释它们对他汀类药物的敏感性降低。这些结果首次表明，密切相关的Rap1a和Rap1b亚型具有不同的功能，并表明他汀类药物或Rap1b耗竭可用于减少T-ALL的组织侵袭。J. Leukoc. 89：577 - 586; 2011.
Statins are known to inhibit signaling of Ras superfamily GTPases and reduce T cell adhesion to ICAM-1. Here, we address the hypothesis that statins affect T cell adhesion and migration by modulating the function of specific GTPases. Statins inhibit the synthesis of mevalonic acid, which is required for farnesyl and geranylgeranyl isoprenoid synthesis. Ras superfamily GTPases are post-translationally isoprenylated to facilitate their anchorage to membranes, where they function to stimulate signal transduction processes. We demonstrate that 1 mu M statin inhibits the adhesion, migration, and chemotaxis of the T-ALL cell line CCRF-CEM and TEM of CCRF-CEM and PEER T-ALL cells, but higher statin concentrations are needed to inhibit adhesion of primary T cells. Similar effects are observed following treatment with GGTI-298 or RNA interference-mediated knockdown of Rap1b but not Rap1a, Rac1, Rac2, RhoA, or Cdc42. Statins also alter Rap1 activity and Rap1b localization. Rap1 levels are higher in primary T cells than T-ALL cells, which could explain their reduced sensitivity to statins. These results demonstrate for the first time that the closely related Rap1a and Rap1b isoforms have different functions and suggest that statins or Rap1b depletion could be used to reduce tissue invasion in T-ALL. J. Leukoc. Biol. 89: 577-586; 2011.