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Blockage of conformational changes of heat shock protein gp96 on cell membrane by a ?-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 ?-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.

SUBMITTER: Li X

PROVIDER: S-EPMC4405268 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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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.

Li Xin X Wang Baozhong B Liu Weiwei W Gui Mingming M Peng Zheng Z Meng Songdong S

PloS one 20150421 4

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 dimeriza ...[more]

PMID: 25898135

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Project description:The extracellular form of the abundant heat-shock protein, gp96, is involved in human autoimmune pathologies. In patients with type 1 diabetes, circulating gp96 is found to be elevated, and is bound to the acute-phase protein, ?1-antitrypsin (AAT). The two molecules also engage intracellularly during the physiological folding of AAT. AAT therapy promotes pancreatic islet survival in both transplantation and autoimmune diabetes models, and several clinical trials are currently examining AAT therapy for individuals with type 1 diabetes. However, its mechanism of action is yet unknown. Here, we examine whether the protective activity of AAT is related to binding of extracellular gp96. Primary mouse islets, macrophages, and dendritic cells were added recombinant gp96 in the presence of clinical-grade human AAT (hAAT, Glassia™, Kamada Ltd., Israel). Islet function was evaluated by insulin release. The effect of hAAT on IL-1?/IFN?-induced gp96 cell-surface levels was also evaluated. In vivo, skin transplantation was performed for examination of robust immune responses, and systemic inflammation was induced by cecal puncture. Endogenous gp96 was inhibited by gp96-inhibitory peptide (gp96i, Compugen Ltd., Israel) in an allogeneic islet transplantation model. Our findings indicate that hAAT binds to gp96 and diminishes gp96-induced inflammatory responses; e.g., hAAT-treated gp96-stimulated islets released less pro-inflammatory cytokines (IL-1? by 6.16-fold and TNF? by 2.69-fold) and regained gp96-disrupted insulin release. hAAT reduced cell activation during both skin transplantation and systemic inflammation, as well as lowered inducible surface levels of gp96 on immune cells. Finally, inhibition of gp96 significantly improved immediate islet graft function. These results suggest that hAAT is a regulator of gp96-mediated inflammatory responses, an increasingly appreciated endogenous damage response with relevance to human pathologies that are exacerbated by tissue injury.

Dataset Information

Blockage of conformational changes of heat shock protein gp96 on cell membrane by a ?-helix peptide inhibits HER2 dimerization and signaling in breast cancer.

Publications

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.

Similar Datasets

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