合成三萜类化合物靶向 Arp2/3 复合物并抑制分支状肌动蛋白聚合。
Synthetic triterpenoids target the Arp2/3 complex and inhibit branched actin polymerization.
机构信息
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
出版信息
J Biol Chem. 2010 Sep 3;285(36):27944-57. doi: 10.1074/jbc.M110.103036. Epub 2010 Jun 21.
Abstract
Synthetic triterpenoids are anti-tumor agents that affect numerous cellular functions including apoptosis and growth inhibition. Here, we used mass spectrometric and protein array approaches and uncovered that triterpenoids associate with proteins of the actin cytoskeleton, including actin-related protein 3 (Arp3). Arp3, a subunit of the Arp2/3 complex, is involved in branched actin polymerization and the formation of lamellipodia. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-Im and CDDO-Me were observed to 1) inhibit the localization of Arp3 and actin at the leading edge of cells, 2) abrogate cell polarity, and 3) inhibit Arp2/3-dependent branched actin polymerization. We confirmed our drug effects with siRNA targeting of Arp3 and observed a decrease in Rat2 cell migration. Taken together, our data suggest that synthetic triterpenoids target Arp3 and branched actin polymerization to inhibit cell migration.
摘要
合成三萜类化合物是抗肿瘤药物，可影响包括细胞凋亡和生长抑制在内的多种细胞功能。在这里，我们使用质谱和蛋白质阵列方法发现三萜类化合物与肌动蛋白细胞骨架的蛋白质（包括肌动蛋白相关蛋白 3 (Arp3)）相关联。Arp3 是 Arp2/3 复合物的一个亚基，参与分支肌动蛋白聚合和片状伪足的形成。观察到 2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸 (CDDO)-Im 和 CDDO-Me：1) 抑制 Arp3 和肌动蛋白在细胞前缘的定位；2) 破坏细胞极性；3) 抑制 Arp2/3 依赖性分支肌动蛋白聚合。我们通过靶向 Arp3 的 siRNA 证实了我们的药物作用，并观察到 Rat2 细胞迁移减少。总之，我们的数据表明，合成三萜类化合物靶向 Arp3 和分支肌动蛋白聚合以抑制细胞迁移。
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