The single N-glycan deletion mutant of soluble ErbB3 protein attenuates heregulinβ1-induced tumor progression by blocking of the HIF-1 and Nrf2 pathway.
The single N-glycan deletion mutant of soluble ErbB3 protein attenuates heregulinβ1-induced tumor progression by blocking of the HIF-1 and Nrf2 pathway.
复制标题
可溶性 ErbB3 蛋白的单个 N-聚糖缺失突变体通过阻断 HIF-1 和 Nrf2 通路来减弱调蛋白β1 诱导的肿瘤进展。
DOI：
10.1016/j.bbrc.2014.10.086
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Kuroki Y
中科院分区：
文献类型：
--
作者：
Takamiya R;Takahashi M;Uehara Y;Ariki S;Hashimoto J;Hasegawa Y;Kuroki Y
已有文献表明，ErbB3-PI3K-Akt通路的激活与肿瘤的生存和进展有关。我们之前已经证明可溶性ErbB3蛋白的单n聚糖缺失突变体（sErbB3 N418Q）减弱了heregulin β1诱导的ErbB3信号传导。活跃的PI3K-Akt通路增加了缺氧诱导因子(HIF)-1α的核积累，从而激活许多靶基因的转录并驱动癌症进展。在这项研究中，我们重点研究了sErbB3 N418Q突变体对HIF-1α核积累的影响。预处理sErbB3 N418Q突变体可抑制heregulin β1诱导的MCF7细胞中HIF-1α的激活。在其他乳腺癌细胞系T47D和BT474中也得到了类似的结果。有趣的是，这些抑制作用在sErbB3野生型中没有观察到。此外，sErbB3 N418Q突变体预处理可抑制heregulin β1诱导的MCF7细胞的细胞迁移。此外，用heregulin β1孵育也能诱导Nrf2的核积累，sErbB3 N418Q突变体也能降低这种效应，但sErbB3野生型则没有。这些发现表明sErbB3 N418Q突变体通过阻断HIF-1α和Nrf2途径抑制癌细胞的恶性形成。
It has been well documented that activation of the ErbB3–PI3K–Akt pathway is implicated in tumor survival and progression. We previously demonstrated that the single N-glycan deletion mutant of soluble ErbB3 protein (sErbB3 N418Q) attenuates heregulin β1-induced ErbB3 signaling. The active PI3K–Akt pathway augments the nuclear accumulation of hypoxia inducible factor (HIF)-1α, which activates the transcription of many target genes and drives cancer progression. In this study, we focused on the effects of sErbB3 N418Q mutant on nuclear accumulation of HIF-1α. Pretreatment with the sErbB3 N418Q mutant suppressed heregulin β1-induced HIF-1α activation in MCF7 cells. Similar results were also obtained in other breast cancer cell lines, T47D and BT474. Interestingly, these suppressive effects were not observed with the sErbB3 wild type. In addition, pretreatment with the sErbB3 N418Q mutant suppressed the cell migration of MCF7 cells induced by heregulin β1. Furthermore, incubation with heregulin β1 also induced the nuclear accumulation of Nrf2, and this effect was also reduced by the sErbB3 N418Q mutant, but not the sErbB3 wild type. These findings indicated that the sErbB3 N418Q mutant suppressed malignant formation of cancer cells by blocking of the HIF-1α and Nrf2 pathways.