Pgrmc1 (Progesterone Receptor Membrane Component 1) Associates with Epidermal Growth Factor Receptor and Regulates Erlotinib Sensitivity
Pgrmc1 (Progesterone Receptor Membrane Component 1) Associates with Epidermal Growth Factor Receptor and Regulates Erlotinib Sensitivity
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DOI：
10.1074/jbc.m110.134585
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发表时间：
2010-08-06
影响因子：
4.8
通讯作者：
Craven, Rolf J.
中科院分区：
文献类型：
--
作者：
Ahmed, Ikhlas S.;Rohe, Hannah J.;Craven, Rolf J.
肿瘤发生需要多种途径的协同作用，包括刺激增殖和代谢的途径。表皮生长因子受体（EGFR）是一种与癌症进展相关的跨膜受体-酪氨酸激酶，EGFR抑制剂厄洛替尼（erlotinib）和酪氨酸磷酸化抑制剂（tyrphostin）是有效的抗癌治疗剂。Pgrmc 1（孕酮受体膜组分1）是一种细胞色素B（5）相关蛋白，在肿瘤中上调并促进癌症生长。Pgrmc 1及其同源物与细胞信号传导有关，我们在这里发现Pgrmc 1增加了对AG-1478和厄洛替尼的敏感性，增加了质膜EGFR水平，并与EGFR共沉淀。Pgrmc 1与EGFR共定位于细胞质囊泡中，并与EGFR共分离于高密度微粒体中。这些发现具有治疗潜力，因为Pgrmc 1小分子配体抑制多种癌细胞类型的生长，使多种肿瘤细胞系中的EGFR不稳定。EGFR是驱动肿瘤发生的最有效的受体酪氨酸激酶之一，我们的数据支持Pgrmc 1至少部分通过结合EGFR和稳定受体的质膜池来促进几种癌症表型的作用。
Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and metabolism. Epidermal growth factor receptor (EGFR) is a transmembrane receptor-tyrosine kinase that is associated with cancer progression, and the EGFR inhibitors erlotinib/tarceva and tyrphostin/AG-1478 are potent anti-cancer therapeutics. Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b(5)-related protein that is up-regulated in tumors and promotes cancer growth. Pgrmc1 and its homologues have been implicated in cell signaling, and we show here that Pgrmc1 increases susceptibility to AG-1478 and erlotinib, increases plasma membrane EGFR levels, and co-precipitates with EGFR. Pgrmc1 co-localizes with EGFR in cytoplasmic vesicles and co-fractionates with EGFR in high density microsomes. The findings have therapeutic potential because a Pgrmc1 small molecule ligand, which inhibits growth in a variety of cancer cell types, de-stabilized EGFR in multiple tumor cell lines. EGFR is one of the most potent receptor-tyrosine kinases driving tumorigenesis, and our data support a role for Pgrmc1 in promoting several cancer phenotypes at least in part by binding EGFR and stabilizing plasma membrane pools of the receptor.