Flotillin depletion affects ErbB protein levels in different human breast cancer cells
Flotillin depletion affects ErbB protein levels in different human breast cancer cells
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DOI：
10.1016/j.bbamcr.2014.04.013
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发表时间：
2014-09-01
影响因子：
5.1
通讯作者：
Sandvig, Kirsten
中科院分区：
文献类型：
--
作者：
Asp, Nagham;Pust, Sascha;Sandvig, Kirsten
ErbB 3受体是细胞生长和癌变的重要调节因子。在乳腺癌患者中，高达50-70%具有ErbB 3过表达，20-30%显示ErbB 2过表达或扩增。ErbB 3还涉及对由ErbB 1或ErbB 2驱动的用于治疗癌症的几种药物的耐药性的发展。ErbB靶向治疗的主要挑战之一是阻断ErbB 2-ErbB 3致癌受体复合物介导的信号传导。我们分析了flotillin对SKBR 3、MCF 7和MDA-MB-134-VI人乳腺癌细胞中ErbB 3水平和ErbB 2-ErbB 3复合物的调节作用。最近，我们描述了一种干扰乳腺癌中ErbB 2信号传导的机制，并证明了Flotilin支架蛋白与ErbB 2和Hsp 90的分子复合物。在本研究中，发现flotillin与ErbB 3形成分子复合物，即使在不存在ErbB 2或其他ErbB受体的细胞中也是如此。flotillin-1或flotillin-2的耗竭导致ErbB 3的下调和ErbB 2-ErbB 3受体复合物的选择性减少。此外，flotillin-2耗尽导致援助和MAPK信号级联的激活减少，作为flotillin耗尽的功能性后果，乳腺癌细胞表现出受损的细胞migration.Altogether，我们提供的数据证明了一种新的和功能性的作用flotillins在调节ErbB蛋白水平和稳定的ErbB 2-ErbB 3受体复合物。因此，flotillins是致癌ErbB功能的重要调节剂和癌症治疗的潜在靶点。(C)2014爱思唯尔有限公司版权所有。
The ErbB3 receptor is an important regulator of cell growth and carcinogenesis. Among breast cancer patients, up to 50-70% have ErbB3 overexpression and 20-30% show overexpressed or amplified ErbB2. ErbB3 has also been implicated in the development of resistance to several drugs used against cancers driven by ErbB1 or ErbB2. One of the main challenges in ErbB-targeting therapy is to inactivate signaling mediated by ErbB2-ErbB3 oncogenic receptor complexes. We analyzed the regulatory role of flotillins on ErbB3 levels and ErbB2-ErbB3 complexes in SKBR3, MCF7 and MDA-MB-134-VI human breast cancer cells. Recently, we described a mechanism for interfering with ErbB2 signaling in breast cancer and demonstrated a molecular complex of flotillin scaffolding proteins with ErbB2 and Hsp90. In the present study, flotillins were found to be in a molecular complex with ErbB3, even in cells without the presence of ErbB2 or other ErbB receptors. Depletion of either flotillin-1 or flotillin-2 resulted in downregulation of ErbB3 and a selective reduction of ErbB2-ErbB3 receptor complexes. Moreover, flotillin-2 depletion resulted in reduced activation of Aid and MAPK signaling cascades, and as a functional consequence of flotillin depletion, breast cancer cells showed an impaired cell migration.Altogether, we provide data demonstrating a novel and functional role of flotillins in the regulation of ErbB protein levels and stabilization of ErbB2-ErbB3 receptor complexes. Thus, flotillins are crucial regulators for oncogenic ErbB function and potential targets for cancer treatment. (C) 2014 Elsevier B.V. All rights reserved.