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Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer

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 eluci...

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Autores principales: Li, Xin, Wang, Baozhong, Liu, Weiwei, Gui, Mingming, Peng, Zheng, Meng, Songdong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405268/
https://www.ncbi.nlm.nih.gov/pubmed/25898135
http://dx.doi.org/10.1371/journal.pone.0124647
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author Li, Xin
Wang, Baozhong
Liu, Weiwei
Gui, Mingming
Peng, Zheng
Meng, Songdong
author_facet Li, Xin
Wang, Baozhong
Liu, Weiwei
Gui, Mingming
Peng, Zheng
Meng, Songdong
author_sort Li, Xin
collection PubMed
description 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 α-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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spelling pubmed-44052682015-05-07 Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer Li, Xin Wang, Baozhong Liu, Weiwei Gui, Mingming Peng, Zheng Meng, Songdong PLoS One Research Article 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 α-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. Public Library of Science 2015-04-21 /pmc/articles/PMC4405268/ /pubmed/25898135 http://dx.doi.org/10.1371/journal.pone.0124647 Text en © 2015 Li et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Li, Xin
Wang, Baozhong
Liu, Weiwei
Gui, Mingming
Peng, Zheng
Meng, Songdong
Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer
title Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer
title_full Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer
title_fullStr Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer
title_full_unstemmed Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer
title_short Blockage of Conformational Changes of Heat Shock Protein gp96 on Cell Membrane by a α-Helix Peptide Inhibits HER2 Dimerization and Signaling in Breast Cancer
title_sort blockage of conformational changes of heat shock protein gp96 on cell membrane by a α-helix peptide inhibits her2 dimerization and signaling in breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405268/
https://www.ncbi.nlm.nih.gov/pubmed/25898135
http://dx.doi.org/10.1371/journal.pone.0124647
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