Research Progress Of The Role Of Heat Shock Protein Gp96 In Cancer Development And Progression

Glycoprotein 96 (gp96) is a highly conserved and ubiquitous glycoprotein that belongs to the heat shock protein 90 (HSP90) family. It comprises 4 domains: N-terminal domain (NTD), middle domain (MD), C-terminal domain (CTD) and charged linker region (CR). Each domain performs a specific function. NTD containing the nucleotide binding site interacts with and hydrolyzes ATP. MD is involved in client protein recognition, and is the site of constitutive dimerization. The ATP hydrolytic activity of NTD requires cooperative action of CR and MD. The schematic representation of gp96 topology is shown in the main text. An increased expression of gp96 has been reported in multiple cancers. Its upregulation in tumors is closely correlated with poor prognosis and decreased overall survival of patients, indicating that gp96 serves as a potential diagnostic and prognostic biomarker. As a chaperone protein gp96 directs the folding and/or assembly of secreted and membrane proteins. It has a limited client protein profile that is involved in key processes linked with the hallmarks of cancer. Previous studies have shown that cellular gp96 physically interacts with and directs the folding and assembly of several client proteins, including insulin-like growth factors (IGF), integrins, epidermal growth factor receptor-2 (HER2) and Wnt co-receptor LRP6, which are involved in the regulation of cell multiplication, normal tissue differentiation, cancer progression and metastasis. It has been found that gp96 was only expressed on cell surface of malignant tumor but not benign tissues. Cell membrane gp96 is closely associated with cancer cell proliferation, invasion, and metastasis. We further demonstrated that gp96 on cell membrane interacts with HER2, urokinase-type plasminogen activator-receptor (uPAR) or ER-alpha 36. Targeting gp96 by siRNA or a monoclonal antibody for gp96 led to decreased cell growth and invasion, increased apoptosis in vitro, and suppression of tumor growth in vivo, validating cell membrane gp96 as a therapeutic target. At present, the selective small-molecule inhibitors (NECA and PU-WS13), a gp96-specific monoclonal antibody (W9mAb), and an inhibitory gp96-targeted polypeptide (p37) are under development and their potential applications in the tumor targeting therapy are highlighted in this review.