Cellular effects of HER3-specific affibody molecules.
Cellular effects of HER3-specific affibody molecules.
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DOI：
10.1371/journal.pone.0040023
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gedda L
中科院分区：
文献类型：
--
作者：
Göstring L;Malm M;Höidén-Guthenberg I;Frejd FY;Ståhl S;Löfblom J;Gedda L
最近的研究已经认识到表皮生长因子受体HER 3是癌症中的关键参与者，因此该受体作为癌症治疗的靶点越来越受到关注。我们先前已经产生了几种对HER 3受体具有亚纳摩尔亲和力的亲和体分子。在这里，我们研究了两种HER 3特异性亲和体分子Z 05416和Z 05417对不同HER 3过表达癌细胞系的影响。使用流式细胞术和共聚焦显微镜，Affibody分子显示与三种不同细胞系上的HER 3结合。此外，天然配体调蛋白（HRG）的受体结合通过添加亲和体分子而被阻断。此外，两种分子均抑制MCF-7细胞中HRG诱导的HER 3和HER 2磷酸化，以及持续HER 2激活的SKBR-3细胞中的HER 3磷酸化。重要的是，蛋白质印迹分析还显示HRG诱导的下游信号传导通过Ras-MAPK途径以及PI 3 K-Akt途径被Affibody分子阻断。最后，在体外增殖测定中，两种亲和体分子表现出对HRG诱导的癌细胞生长的完全抑制。综上所述，我们的研究结果表明，Z 05416和Z 05417通过抑制HRG诱导的HER 3磷酸化对两种乳腺癌细胞系发挥抗增殖作用，这表明Affibody分子是未来HER 3靶向癌症治疗的有希望的候选者。
Recent studies have led to the recognition of the epidermal growth factor receptor HER3 as a key player in cancer, and consequently this receptor has gained increased interest as a target for cancer therapy. We have previously generated several Affibody molecules with subnanomolar affinity for the HER3 receptor. Here, we investigate the effects of two of these HER3-specific Affibody molecules, Z05416 and Z05417, on different HER3-overexpressing cancer cell lines. Using flow cytometry and confocal microscopy, the Affibody molecules were shown to bind to HER3 on three different cell lines. Furthermore, the receptor binding of the natural ligand heregulin (HRG) was blocked by addition of Affibody molecules. In addition, both molecules suppressed HRG-induced HER3 and HER2 phosphorylation in MCF-7 cells, as well as HER3 phosphorylation in constantly HER2-activated SKBR-3 cells. Importantly, Western blot analysis also revealed that HRG-induced downstream signalling through the Ras-MAPK pathway as well as the PI3K-Akt pathway was blocked by the Affibody molecules. Finally, in an in vitro proliferation assay, the two Affibody molecules demonstrated complete inhibition of HRG-induced cancer cell growth. Taken together, our findings demonstrate that Z05416 and Z05417 exert an anti-proliferative effect on two breast cancer cell lines by inhibiting HRG-induced phosphorylation of HER3, suggesting that the Affibody molecules are promising candidates for future HER3-targeted cancer therapy.
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影响因子：
2.4
作者：
Kronqvist, Nina;Lofblom, John;Stahl, Stefan
通讯作者：
Stahl, Stefan
DOI：
10.1073/pnas.91.17.8132
发表时间：
1994-08-16
影响因子：
11.1
作者：
GUY, PM;PLATKO, JV;CARRAWAY, KL
通讯作者：
CARRAWAY, KL
影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.
影响因子：
2.4
作者：
Kronqvist, Nina;Malm, Magdalena;Lofblom, John
通讯作者：
Lofblom, John