| 论文题目: | Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a alpha-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer |
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| 作者: | Xin Li, Baozhong Wang, Weiwei Liu, Mingming Gui, Zheng* Peng, and Songdong* Meng. |
| 联系作者: | |
| 刊物名称: | PLoS One |
| 期: | 10 |
| 卷: | 4 |
| 页: | e0124647 |
| 年份: | 2015 |
| 影响因子: | 4.015 |
| 论文下载: | 下载地址 |
| 摘要: | Cell membrane translocation of heat shock protein gp96 from the endoplasmic reticulum has been observed in multiple tumors and is associated with tumor malignancy. However, the cancer-intrinsic function and the related mechanism of cell membrane gp96 as a pro-oncogenic chaperone remain further elucidated. In this study, we found that inhibition of gp96 intramolecular conformational changes by a single alpha-helix peptide p37 dramatically increased its binding to HER2, whereas decreased HER2 dimerization, phosphorylation and downstream signaling. Targeting cell membrane gp96 promoted HER2 ubiquitination and subsequent lysosomal degradation, which led to decreased cell growth and increased apoptosis, and inhibited tumor growth in vivo. We also demonstrate that gp96 inhibitory peptide p37 synergized with trastuzumab to suppress cell growth and induce apoptosis. Our work demonstrates that blocking gp96 conformational changes directs HER2 for cellular degradation, and represents a new therapeutic strategy for inhibiting HER2 signaling in cancer. |
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