Effects of HER2-binding affibody molecules on intracellular signaling pathways
Effects of HER2-binding affibody molecules on intracellular signaling pathways
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DOI：
10.1159/000093023
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发表时间：
2006-01-01
期刊：
影响因子：
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通讯作者：
Lennartsson, Johan
中科院分区：
文献类型：
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作者：
Ekerljung, Lina;Steffen, Ann-Charlott;Lennartsson, Johan
背景：HER2在25-30%的人类乳腺癌中过表达，是一种酪氨酸激酶受体，对调节细胞增殖、迁移和凋亡的信号转导网络至关重要。方法：采用定量免疫印迹技术，研究了两种新型her2结合的粘附分子(附着体(R), (Z(HER2:4))(2)和Z（HER2:342）对细胞内信号转导通路（Erk1/2， Akt和PLC 1）的影响及其在细胞培养中的生物学效应。临床批准的抗体曲妥珠单抗（赫赛汀(R)）作为对照品。结果：我们的数据显示，虽然所有物质都靶向HER2，但对受体和信号分子的影响不同。例如，HER2磷酸化可由曲妥珠单抗和（Z(HER2:4)）(2)诱导，但可被Z（HER2:342）抑制。这些物质对信号转导的影响在一定程度上与生长和迁移的变化相关，例如（ZHER2:4）2刺激Erk1/2和PLC γ 1的磷酸化，以及生长和迁移，而ZHER2:342没有。Z（HER2:342）甚至抑制PLC γ - 1的磷酸化和迁移。结论：我们的数据表明，Z（HER2:342）是一种很有前景的小药物（7 kDa），可以用作曲妥珠单抗的替代或补充。如果放射性标记，它也有望用于HER2成像和放射性核素治疗。版权所有(c) 2006 S. Karger AG，巴塞尔。
Background: HER2, which is overexpressed in 25-30% of human breast cancers, is a tyrosine kinase receptor critical for the signal transduction network that regulates proliferation, migration and apoptosis of cells. Method: We report the effects of two novel HER2-binding affibody molecules (Affibody (R)), (Z(HER2:4))(2) and Z(HER2:342), on intracellular signal transduction pathways (Erk1/2, Akt and PLC 1) using quantitative immunoblotting techniques and their biological effects in cell culture. The clinically approved antibody trastuzumab (Herceptin (R)) was used as reference substance. Results: Our data showed that, although all substances target HER2, the effects on the receptor and signaling molecules differed. For example, HER2 phosphorylation was induced by trastuzumab and (Z(HER2:4))(2) but inhibited by Z(HER2:342). The effects these substances had on signal transduction correlated to some degree with changes in growth and migration, e.g. (ZHER2:4)2 stimulated phosphorylation of Erk1/2 and PLC gamma 1, as well as growth and migration, while ZHER2:342 did not. Z(HER2:342) even inhibited phosphorylation of PLC gamma 1 and migration. Conclusion: Our data suggest that Z(HER2:342) is a promising small agent (7 kDa) that may be used as an alternative, or complement, to trastuzumab. If radiolabelled, it can hopefully also be used for HER2 imaging and radionuclide therapy. Copyright (c) 2006 S. Karger AG, Basel.