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

Xin Li; Baozhong Wang; Weiwei Liu; Mingming Gui; Zheng Peng; Songdong Meng

doi:10.1371/journal.pone.0124647

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

PLoS One. 2015 Apr 21;10(4):e0124647. doi: 10.1371/journal.pone.0124647. eCollection 2015.

Authors

Xin Li¹, Baozhong Wang², Weiwei Liu¹, Mingming Gui³, Zheng Peng⁴, Songdong Meng³

Affiliations

¹ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
² School of Life Sciences, Anhui University, Hefei, China.
³ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
⁴ Chinese People's Liberation Army General Hospital, Beijing, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antigens, Neoplasm / genetics*
Antigens, Neoplasm / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Endoplasmic Reticulum / drug effects
Endoplasmic Reticulum / metabolism
Female
Gene Expression Regulation, Neoplastic*
Humans
Mice
Molecular Sequence Data
Peptides / chemical synthesis
Peptides / pharmacology*
Phosphorylation / drug effects
Protein Binding / drug effects
Protein Conformation / drug effects
Protein Multimerization / drug effects
Protein Transport / drug effects
Proteolysis / drug effects
Receptor, ErbB-2 / antagonists & inhibitors*
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism
Signal Transduction
Trastuzumab / pharmacology
Ubiquitination / drug effects
Xenograft Model Antitumor Assays

Substances

Antigens, Neoplasm
Antineoplastic Agents
Peptides
sarcoma glycoprotein gp96 rejection antigens
ERBB2 protein, human
Receptor, ErbB-2
Trastuzumab

Grants and funding

This work was supported by a grant from Major State Basic Research Development Program of China (973 Program, No.2014CB542602), grants from the National Natural Science Foundation of China (31230026, 81321063, 81102018, 81471960), and grants from Key Projects in the National Science & Technology Program (2013ZX10002001-003-003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.