Oligopeptides derived from autophosphorylation sites of EGF receptor suppress EGF-stimulated responses in human lung carcinoma A549 cells.
Oligopeptides derived from autophosphorylation sites of EGF receptor suppress EGF-stimulated responses in human lung carcinoma A549 cells.
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源自 EGF 受体自身磷酸化位点的寡肽可抑制人肺癌 A549 细胞中 EGF 刺激的反应。
DOI：
10.1016/j.ejphar.2012.10.007
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发表时间：
2013
期刊：
影响因子：
5
通讯作者：
Hirose M
中科院分区：
文献类型：
--
作者：
Kuroda Y;Kato-Kogoe N;Tasaki E;Murata M;Ueda K;Abe M;Miyamoto K;Nakase I;Futaki S;Tohyama Y;Hirose M
表皮生长因子（EGF）受体在人类癌症的生物学中起着至关重要的作用，并且是非常合适的抗癌药物的靶点。我们以前设计的寡肽含有的氨基酸序列周围的自磷酸化位点的EGF受体，以确定这种受体的特异性抑制剂。Ac-ENAEYLR-NH_2和Ac-NYQQN-NH_2以非ATP竞争性方式抑制纯化的EGF受体的磷酸化，而Ac-QNAQYLR-NH_2和Ac-DYQQ-NH_2则以ATP竞争性方式抑制EGF受体的磷酸化。本研究的目的是观察这些肽对人肺癌A549细胞增殖、细胞死亡和凋亡的影响。为了促进这些抑制肽转移到A549细胞中，将细胞穿透肽，人免疫缺陷病毒1型转录反式激活因子（达特）连接到肽上。当A549细胞用每种Tat缀合的肽处理时，肽穿透细胞并且EGF刺激的EGF受体的酪氨酸磷酸化被显著抑制。这些Tat结合肽在EGF刺激的A549细胞反应中起抑制作用。Tat-acp-DYQQD-NH 2和Tat-acp-NYQQN-NH 2抑制EGF的抗凋亡作用。此外，我们发现Tat-acp-ENAEYLR-NH_2还抑制了A549细胞表皮生长因子受体2（ErbB_2）和EGF受体的磷酸化。总之，来自EGF受体自磷酸化位点的膜渗透性合成肽具有抑制A549细胞中EGF受体功能的潜力，并将被开发成用于癌症治疗的新型和有用的药剂。
Epidermal growth factor (EGF) receptor plays a crucial role in the biology of human cancer, and is a highly appropriate target for anticancer agents. We have previously designed oligopeptides containing the amino acid sequences around autophosphorylation sites of EGF receptor to identify a specific inhibitor of this receptor. We found that Ac-ENAEYLR-NH2and Ac-NYQQN-NH2suppressed phosphorylation of purified EGF receptor in a non-ATP-competitive manner whereas Ac-QNAQYLR-NH2and Ac-DYQQD-NH2caused inhibition in an ATP-competitive manner. The aim of this study was to observe the effects of these peptides on the proliferation, cell death, and apoptosis of human lung carcinoma A549 cells. To facilitate transfer of these inhibitory peptides into A549 cells, the cell-penetrating peptide, human immunodeficiency virus type 1-transactivator of transcription (Tat), was linked to the peptides. When A549 cells were treated with each Tat-conjugated peptide, the peptides penetrated the cells and EGF-stimulated tyrosine phosphorylation of EGF receptor was significantly suppressed. These Tat-conjugated peptides played a suppressive role in EGF-stimulated A549 cell responses. In particular, Tat-epsilon-aminocaproic acid (acp)-ENAEYLR-NH2significantly inhibited proliferation and showed cytotoxicity, while Tat-acp-NYQQN-NH2and Tat-acp-DYQQD-NH2suppressed the anti-apoptotic effect of EGF. In addition, we found that Tat-acp-ENAEYLR-NH2also inhibited the phosphorylation of epidermal growth factor receptor 2 (ErbB2) as well as EGF receptor in A549 cells. In conclusion, membrane-permeable synthetic peptides derived from EGF receptor autophosphorylation sites have the potential to suppress EGF receptor function in A549 cells and to be developed into novel and useful agents for cancer therapy.