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首页> 外文期刊>Cancer science. >Biasing human epidermal growth factor receptor 4 (HER4) tyrosine kinase signaling with antibodies: Induction of cell death by antibody‐dependent HER4 intracellular domain trafficking
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Biasing human epidermal growth factor receptor 4 (HER4) tyrosine kinase signaling with antibodies: Induction of cell death by antibody‐dependent HER4 intracellular domain trafficking

机译：偏置人表皮生长因子受体4（HER4）抗体酪氨酸激酶信号传导：通过抗体依赖性HER4细胞内域贩运诱导细胞死亡

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Human epidermal growth factor receptor 4 (HER4) isoforms have oncogenic or tumor suppressor functions depending on their susceptibility to proteolytic cleavage and HER4 intracellular domain (4ICD) translocation. Here, we report that the neuregulin 1 (NRG1) tumor suppressor mechanism through the HER4 JMa/CYT1 isoform can be mimicked by the agonist anti‐HER4 Ab C6. Neuregulin 1 induced cleavage of poly(ADP‐ribose) polymerase (PARP) and sub‐Gsub1/sub DNA fragmentation, and also reduced the metabolic activity of HER3sup?/sup/HER4sup+/sup cervical (C‐33A) and ovarian (COV318) cancer cells. This effect was confirmed in HER4 JMa/CYT1‐, but not JMa/CYT2‐transfected BT549 triple‐negative breast cancer cells. Neuregulin 1 favored 4ICD cleavage and retention in mitochondria in JMa/CYT1‐transfected BT549 cells, leading to reactive oxygen species (ROS) production through mitochondrial depolarization. Similarly, the anti‐HER4 Ab C6, which binds to a conformational epitope located on a.a. 575‐592 and 605‐620 of HER4 domain IV, induced 4ICD cleavage and retention in mitochondria, and mimicked NRG1‐mediated effects on PARP cleavage, ROS production, and mitochondrial membrane depolarization in cancer cells. In vivo, C6 reduced growth of COV434 and HCC1187 tumor cell xenografts in nude mice. Biasing 4ICD trafficking to mitochondria with anti‐HER4 Abs to mimic NRG1 suppressor functions could be an alternative anticancer strategy.
机译：人表皮生长因子受体4（HER4）同种型具有致癌或肿瘤抑制剂，这取决于它们对蛋白水解裂解和HER4细胞内结构粒子（4IMD）易位的敏感性。在这里，我们报道了通过HER4 JMA / CYT1同种型的Neuregulin 1（NRG1）肿瘤抑制机制可以由激动剂抗HER4 AB C6模拟。 Neuregulin 1诱导聚（ADP-核糖）聚合酶（PARP）和Sub-G 1 DNA碎片的切割，并且还降低了HER3 / HER4 + / sup>宫颈（C-33a）和卵巢（CoV318）癌细胞。这种效果在HER4 JMA / CYT1-中确认，但不是JMA / CYT2转染的BT549三阴性乳腺癌细胞。 Neuregulin 1赞成4分裂解和在Jma / Cyt1转染的BT549细胞中的线粒体保留，导致通过线粒体去极化的活性氧物质（ROS）产生。类似地，抗HER4AB C6，其与位于A.A的构象表位结合。 HER4结构域IV的575-592和605-620，在线粒体诱导4分析和保留，并模仿NRG1介导对PARP切割，ROS生产和线粒体膜去极化的影响。体内，C6在裸鼠中降低CoV434和HCC1187肿瘤细胞异种移植物的生长。将4个贩运线粒体偏向线粒体与抗HERM4 ABS进行模拟NRG1抑制功能可能是替代抗癌策略。

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