![]() Peptides chaperoned by GRP94 can be presented to cytotoxic T lymphocytes and initiate antigen-specific T-cell responses to cancer. (C) Surface GRP94 is involved in DC maturation via a cell surface receptor CD91. The increase of GRP94 is responsible for strengthening pro-survival signaling to promote tumor cell survival and aggression. However, when the UPR is prolonged, it can also result in cell death through apoptosis and autophagy. Activation of UPR leads to the up-regulation of pro-survival signaling involved in angiogenesis, folding capacity, redox protection, and degradation of unfolded proteins to keep the cell surviving. (B) Both intrinsic and extrinsic stress conditions exist in the tumor microenvironment and trigger ER stress and UPR. (A) Major clients of GRP94 and its role in different signaling pathways. GRP94 plays a critical role in regulating the balance between cancer cell survival and death through sustaining ER protein folding capacity, maintaining ER stress sensors, and repressing ER-associated pro-apoptotic machinery ( Figure 1B).įigure 1 GRP94 major client network, the role of GRP94 in balancing cancer-induced ER stress responses, and immune regulation in the tumor microenvironment. However, when the activation of this response is prolonged, it can also result in cell death. Activation of the unfolded protein response (UPR) leads to the up-regulation of pro-survival proteins involved in angiogenesis, folding capacity, redox protection, or degradation of unfolded proteins ( 4). A wide range of stressful conditions exists within the tumor microenvironment, including hypoxia, redox homeostasis dysregulation, altered cell metabolism, acidosis, and genetic lesions leading to the production of mutated proteins, high rates of proliferation, and increased protein synthesis ( 3). GRP94 is upregulated in many stress conditions that disturb endoplasmic reticulum (ER) homeostasis ( 2). Glucose regulated protein 94 (GRP94), also known as GP96, is a stress-inducible molecular chaperone that belongs to the heat shock protein (HSP) 90 family ( 1). Finally, we will briefly review the therapeutic potential of selectively targeting GRP94 for the treatment of cancers. In this review, we will undergo deep molecular profiling of GRP94 in tumor development and summarize the individual roles of GRP94 in common cancers, including breast cancer, colon cancer, lung cancer, liver cancer, multiple myeloma, and others. Thus, GRP94 is a potential molecular marker and therapeutic target in malignancies. Clinically, elevated expression of GRP94 correlates with an aggressive phenotype and poor clinical outcome in a variety of cancers. ![]() ![]() Heat shock protein (HSP) GRP94, also known as GP96, is an ER paralog of HSP90 and has been shown to promote survival signaling during tumor-induced stress and modulate the immune response through its multiple clients, including TLRs, integrins, LRP6, GARP, IGF, and HER2. 4The Pelotonia Institute for Immuno-Oncology at The Ohio State University Comprehensive Cancer Center, Columbus, OH, United Statesĭuring tumor development and progression, intrinsic and extrinsic factors trigger endoplasmic reticulum (ER) stress and the unfolded protein response, resulting in the increased expression of molecular chaperones to cope with the stress and maintain tumor cell survival.3Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin Clinical Research Center for Cancer, Tianjin, China.2Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States.1Department of Microbiology & Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.Xiaofeng Duan 1† Stephen Iwanowycz 1† Soo Ngoi 2 Megan Hill 2 Qiang Zhao 3 Bei Liu 1,2,4* ![]()
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