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.
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.
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Life Sciences, Anhui University, Hefei, China.
authors.forename: Baozhong
authors.initials: B
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Gui
authors.affiliation: Chinese People's Liberation Army General Hospital, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Peng
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
authors.forename: Songdong
authors.initials: S
authors.lastname: Meng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000068878:Trastuzumab / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C052646:sarcoma glycoprotein gp96 rejection antigens; C508053:ERBB2 protein, human