Cell Surface GRP78 as a Death Receptor and an Anticancer Drug Target

Cell surface GRP78 (csGRP78, glucose-regulated protein 78 kDa) is preferentially overexpressed in aggressive, metastatic, and chemo-resistant cancers. GRP78 is best studied as a chaperone protein in the lumen of endoplasmic reticulum (ER), facilitating folding and secretion of the newly synthesized proteins and regulating protein degradation as an ER stress sensor in the unfolded protein pathway. As a cell surface signal receptor, multiple csGRP78 ligands have been discovered to date, and they trigger various downstream cell signaling pathways including pro-proliferative, pro-survival, and pro-apoptotic pathways. In this perspective, we evaluate csGRP78 as a cell surface death receptor and its prospect as an anticancer drug target. The pro-apoptotic ligands of csGRP78 discovered so far include natural proteins, monoclonal antibodies, and synthetic peptides. Even the secreted GRP78 itself was recently found to function as a pro-apoptotic ligand for csGRP78, mediating pancreatic β-cell death. As csGRP78 is found to mainly configur as an external peripheral protein on cancer cell surface, how it can transmit death signals to the cytoplasmic environment remains enigmatic. With the recent encouraging results from the natural csGRP78 targeting pro-apoptotic monoclonal antibody PAT-SM6 in early-stage cancer clinical trials, the potential to develop a novel class of anticancer therapeutics targeting csGRP78 is becoming more compelling.