The ER Chaperone GRP78 and Cancer

The unfolded protein response (UPR) is emerging as a major contributor to cancer cell adaptation to the pathophysiological stress of tumorigenesis. As a major endoplasmic reticulum (ER) chaperone, GRP78/BiP is induced by the UPR, and functions as a master regulator of the UPR signaling pathways. In this review, recent global analysis of Grp78 mRNA level in specific human tissues and its role in ER stress signaling and cell survival are discussed. Very recently the dynamic molecular events during the transcriptional induction of Grp78 were elucidated, providing kinetics of factor occupancy along the Grp78 promoter in cells subjected to ER stress. In addition to its established function of an apoptotic protein, a regulatory role of GRP78 in stress-induced autophagy in mammalian cells is also recently defined. In multiple cancer models, both in vitro and in vivo, GRP78 confers growth advantage and drug resistance to solid tumors. Finally, the newly discovered cell surface GRP78 provides potential cancer specific therapy.