Immunotherapy with heat shock protein 96 to treat gliomas
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中华医学会神经外科学分会 CHINESE MEDICAL ASSOCIATION
CHINESE NEUROSURGICAL SOCIETY
REVIEW
Open Access
Immunotherapy with heat shock protein 96 to treat gliomas Chunzhao Li1†, Yifei Du2†, Yang Zhang1,3,4 and Nan Ji1,3,4*
Abstract Heat shock protein 96 (gp96) is a highly conserved protein in the endoplasmic reticulum. The functions of gp96 include promoting the oncogenesis and progression of glioma. In addition, tumor-derived gp96 can activate antitumor immune. Therefore, this protein was used to generate an anti-tumor vaccine and widely applied to glioma therapy. This review summarizes the mechanisms of gp96 in glioma oncogenesis and clinical trials of the gp96 tumor vaccine in glioma treatment. Keywords: Glioma, gp96, Tumor vaccine, Oncogenesis
Background Heat shock protein glycoprotein 96 kDa (gp96) is also named glucose-regulated protein 94 (GRP94), endoplasmic reticulum protein 99 (ERp99), and heat shock protein 90 b1 (HSP90b1). As with other heat shock proteins, gp96 expression was significantly increased when the cells were stimulated by hyperthermia, hypoxia, infection, or poisoning. However, because gp96 plays a key role in glioma oncogenesis and anti-tumor immune regulation, it became a therapy for glioma. Structure and physiological function of gp96 When classified by its protein molecular weight, gp96 is one of five proteins, with HSP90AA1, HSP90AA2, HSP90AB1, and HSP90L, in the HSP90 family with 50% shared homology. Their structures are conserved and primarily consist of four structural domains: an Nterminal domain, a C-terminal domain, a charged linker * Correspondence: [email protected] Chunzhao Li and Yifei Du contribute equally to this work. 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.119 South 4th Ring West Road, Fengtai District, Beijing 100070, China 3 China National Clinical Research Center Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No.119 South 4th Ring West Road, Fengtai District, Beijing 100070, China Full list of author information is available at the end of the article
region, and a middle domain. Gp96 exerts its functions by binding a variety of proteins in each domain [1]. The primary physiological function of gp96 is facilitation of protein folding, quality control in the endoplasmic reticulum (ER), and regulating Ca2+ in cells.
Facilitating protein folding and ER quality control
The endoplasmic reticulum is an organelle where proteins are synthesized, folded, and transported and is the primary site for posttranscriptional protein modification. Gp96 is a resident protein of the ER that facilitates protein folding and assembly in the ER [2]. However, protein folding is actually an inefficient process that results in many unfolded proteins, which can lead to genetic disease, including diabetes, when accumulated over a specific concentration [3]. The overexpression of unfolded protein in the ER can upregulate the expression of gp96. This upregulation leads to the elevated expression of chaperone protein and the sign
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