Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

The glucose-regulated proteins (GRPs) GRP78, GRP94, GRP170 and GRP75, are members of the heat shock protein family. They primarily reside in the endoplasmic reticulum (ER) or the mitochondria, and they are induced at the transcriptional level upon ER stress.As molecular chaperones, the GRPs regulate protein quality control and degradation, with GRP78 additionally functioning as a pivotal regulator of the unfolded protein response and the apoptotic machinery that is associated with the ER.The GRPs can be actively translocated to other cellular locations and secreted, and they can assume additional functions that control cellular signalling, proliferation, invasion, apoptosis, inflammation and immunity, which have major implications in cancer progression and therapeutic resistance.Specific roles of GRPs in development, tumorigenesis, metastasis and angiogenesis have been identified in vitro and are supported by genetically engineered mouse models.GRP overexpression is widely reported in many human cancers and is associated with aggressive properties, which suggests that GRPs have potential prognostic value. Interfering with the production or activities of GRPs in tumours that overexpress these proteins might provide new approaches for cancer treatment.The discovery that cell surface GRP78 is preferably expressed in cancer cells and stressed endothelial cells has led to the development of therapeutic agents that specifically target cell surface GRP78. These agents can induce cancer cell apoptosis and suppress tumorigenesis in mouse models with minimal toxicity.Although the GRPs are attractive targets for drug development, they can also function as mediators for cancer-specific drug delivery, transcriptional targeting of cancer and vaccine development.GRP170 can present full-length antigens to induce an immune response, which suggests that GRP170 could function as part of a new vaccine platform to augment antitumour immune responses.