Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy.
Caveolin-1 mediates cellular distribution of HER2 and affects trastuzumab binding and therapeutic efficacy.
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DOI：
10.1038/s41467-018-07608-w
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发表时间：
2018-12-03
影响因子：
16.6
通讯作者：
Lewis JS
中科院分区：
文献类型：
--
作者：
Pereira PMR;Sharma SK;Carter LM;Edwards KJ;Pourat J;Ragupathi A;Janjigian YY;Durack JC;Lewis JS
肿瘤中人表皮生长因子受体2 （HER2）基因扩增和/或蛋白过表达是曲妥珠单抗治疗开始的先决条件。虽然HER2是一种细胞膜受体，但不同速率的内吞作用和再循环产生了一个动态的HER2表面池。由于曲妥珠单抗必须与HER2的细胞外结构域结合，HER2表面池的抑制阻碍了结合。通过体内生物模型和新鲜人肿瘤的培养，我们发现在受体内吞作用的背景下，CAV1蛋白参与了HER2细胞膜动力学。我们的观察结果强调了这一发现的翻译意义，即洛伐他汀暂时耗尽CAV1增加了HER2的半衰期和细胞膜上的可用性，从而改善了曲妥珠单抗结合和治疗HER2阳性肿瘤。这些数据表明，CAV1在曲妥珠单抗靶向her2阳性肿瘤的有效性中起着重要作用。曲妥珠单抗与肿瘤细胞的结合取决于HER2在细胞膜上的可用性。在这里，作者表明，CAV1调节细胞膜上的HER2密度，并且通过胆固醇调节剂洛伐他汀，CAV1基因敲低或蛋白消耗增加曲妥珠单抗结合和抗肿瘤活性。
Human epidermal growth factor receptor 2 (HER2) gene amplification and/or protein overexpression in tumors is a prerequisite for initiation of trastuzumab therapy. Although HER2 is a cell membrane receptor, differential rates of endocytosis and recycling engender a dynamic surface pool of HER2. Since trastuzumab must bind to the extracellular domain of HER2, a depressed HER2 surface pool hinders binding. Using in vivo biological models and cultures of fresh human tumors, we find that the caveolin-1 (CAV1) protein is involved in HER2 cell membrane dynamics within the context of receptor endocytosis. The translational significance of this finding is highlighted by our observation that temporal CAV1 depletion with lovastatin increases HER2 half-life and availability at the cell membrane resulting in improved trastuzumab binding and therapy against HER2-positive tumors. These data show the important role that CAV1 plays in the effectiveness of trastuzumab to target HER2-positive tumors. Trastuzumab binding to tumor cells depends on the availability of HER2 at the cell membrane. Here the authors show that caveolin-1 (CAV1) regulates HER2 density at the cell membranes and that CAV1 gene knockdown or protein depletion via the cholesterol modulator lovastatin, increases trastuzumab binding and anti-tumor activity.
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DOI：
10.1016/j.bbrc.2013.03.062
发表时间：
2013-04-26
影响因子：
3.1
作者：
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通讯作者：
Leung, Peter C. K.
影响因子：
16
作者：
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影响因子：
64.8
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影响因子：
64.8
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影响因子：
16.6
作者：
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通讯作者：
Sliwkowski, Mark X.