Institut für Biochemie und Molekularbiologie I, Zelluläre Signaltransduktion, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
J Biol Chem. 2010 Feb 19;285(8):5541-54. doi: 10.1074/jbc.M109.047050. Epub 2009 Dec 17.
Cellular migration is an essential prerequisite for metastatic dissemination of cancer cells. This study demonstrates that the neuron/testis-specific F-actin-targeted inositol 1,4,5-trisphosphate 3-kinase-A (ITPKA) is ectopically expressed in different human tumor cell lines and during tumor progression in the metastatic tumor model Balb-neuT. High expression of ITPKA increases invasive migration in vitro and metastasis in a xenograft SCID mouse model. Mechanistic studies show that ITPKA promotes migration of tumor cells by two different mechanisms as follows: growth factor independently high levels of ITPKA induce the formation of large cellular protrusions by directly modulating the actin cytoskeleton. The F-actin binding activity of ITPKA stabilizes and bundles actin filaments and thus increases the levels of cellular F-actin. In growth factor-stimulated cells, the catalytically active domain enhances basal ITPKA-induced migration by activating store-operated calcium entry through production of inositol 1,3,4,5-tetrakisphosphate and subsequent inhibition of inositol phosphate 5-phosphatase. These two functional activities of ITPKA stimulating tumor cell migration place the enzyme among the potential targets of anti-metastatic therapy.
细胞迁移是癌细胞转移扩散的必要前提。本研究表明，神经元/睾丸特异性 F-肌动蛋白靶向肌醇 1,4,5-三磷酸 3-激酶-A（ITPKA）在不同的人肿瘤细胞系中以及在转移性肿瘤模型 Balb-neuT 中的肿瘤进展过程中异位表达。ITPKA 的高表达增加了体外侵袭性迁移和异种移植 SCID 小鼠模型中的转移。机制研究表明，ITPKA 通过两种不同的机制促进肿瘤细胞的迁移：生长因子独立的高水平 ITPKA 通过直接调节肌动蛋白细胞骨架诱导大细胞突起的形成。ITPKA 与 F-肌动蛋白的结合活性稳定并束状肌动蛋白丝，从而增加细胞 F-肌动蛋白的水平。在生长因子刺激的细胞中，通过产生肌醇 1,3,4,5-四磷酸并随后抑制肌醇磷酸 5-磷酸酶，催化活性结构域增强了 ITPKA 诱导的基础迁移，从而激活储存操纵的钙内流。ITPKA 刺激肿瘤细胞迁移的这两种功能活性将该酶置于抗转移治疗的潜在靶点之间。
