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Cancer cells adapt to chronic stress in the tumor microenvironment by inducing the expression of GRP78/BiP, a major endoplasmic reticulum chaperone with Ca 2+ -binding and antiapoptotic properties. GRP78 promotes tumor proliferation, survival, metastasis, and resistance to a wide variety of therapies. Thus, GRP78 expression may serve as a biomarker for tumor behavior and treatment response. Combination therapy suppressing GRP78 expression may represent a novel approach toward eradication of residual tumors. Furthermore, the recent discovery of GRP78 on the cell surface of cancer cells but not in normal tissues suggests that targeted therapy against cancer via surface GRP78 may be feasible. [Cancer Res 2007;67(8):3496-9] Endoplasmic Reticulum Stress and CancerThe endoplasmic reticulum (ER) is an essential perinuclear organelle for the synthesis and folding of secretory and membrane proteins, which accounts for about one third of the cell's proteins. When the protein load exceeds the folding capacity of the ER, the cells trigger the unfolded protein response (UPR), which activates the PERK, IRE1/X-box binding protein-1 (XBP-1), and activating transcription factor-6 (ATF6) signaling pathways as protective measures, resulting in general translational attenuation, up-regulation of chaperones and folding enzymes, and enhanced ER-associated degradation of malfolded proteins (1, 2). Depending on the severity of ER stress, the UPR can result in cell death through the activation of apoptotic pathways mediated specifically by the ER, as well as coupling with the mitochondrial pathways (2, 3). ER stress also induces autophagy, a cellular degradation process implicated in both cell death and survival (4).Cancer cells are subject to ER stress because of both intrinsic and extrinsic factors (5). Cancer cells exhibit elevated glucose metabolism with increased glycolytic activity, and solid tumors often grow faster than their blood supply. The latter creates a tumor microenvironment characterized by glucose deprivation, acidosis, and severe hypoxia. These combined factors leads to the accumulation of underglycosylated and misfolded proteins in the ER, triggering the UPR (Fig. 1). In xenograft models, XBP-1 is required for survival under hypoxic conditions and tumor growth, whereas PERK confers advantage for tumor growth (6, 7). Another major UPR adaptive survival response is the induction of ER chaperone GRP78 in the tumor microenvironment (Fig. 1), which is the focus of this review. GRP78 Is a Key Survival Factor in Development and CancerThe glucose-regulated protein GRP78, also referred to as BiP (immunoglobulin heavy-chain binding protein), was discovered in the late 1970s together with GRP94 and GRP58 as cellular proteins induced by glucose starvation (1). Residing primarily in the ER, GRP78 belongs to the HSP70 protein family, which plays critical roles in the stress of oncogenesis. In addition to facilitating proper protein folding, preventing intermediates from aggregating, and targeting misfolded protein for p...

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Preface The glucose regulated proteins (GRPs) are stress inducible chaperones majorly residing in the endoplasmic reticulum (ER) and the mitochondria. Recent advances reveal that the GRPs serve distinct functions from the related heat shock proteins (HSPs), and they can be actively translocated to other cellular locations and assume novel functions controlling signaling, proliferation, invasion, apoptosis, inflammation and immunity. Mouse models further identified their specific roles in development, tumorigenesis, metastasis and angiogenesis. This Review describes their discovery, regulation and their biological functions in cancer. Promising agents using or targeting the GRPs are being developed, and their efficacy as anti-cancer therapeutics is also discussed.

A large number of correlative studies have established that the activation of the unfolded protein response (UPR) alters the cell's sensitivity to chemotherapeutic agents. Although the induction of the glucose-regulated proteins (GRPs) is commonly used as an indicator for the UPR, the direct role of the GRPs in conferring resistance to DNA damaging agents has not been proven. We report here that without the use of endoplasmic reticulum (ER) stress inducers, specific overexpression of GRP78 results in reduced apoptosis and higher colony survival when challenged with topoisomerase II inhibitors, etoposide and doxorubicin, and topoisomerase I inhibitor, camptothecin. While investigating the mechanism for the GRP78 protective effect against etoposideinduced cell death, we discovered that in contrast to the UPR, GRP78 overexpression does not result in G 1 arrest or depletion of topoisomerase II. Caspase-7, an executor caspase that is associated with the ER, is activated by etoposide. We show here that specific expression of GRP78 blocks caspase-7 activation by etoposide both in vivo and in vitro, and this effect can be reversed by addition of dATP in a cell-free system. Recently, it was reported that ectopically expressed GRP78 and caspases-7 and -12 form a complex, thus coupling ER stress to the cell death program. However, the mechanism of how GRP78, a presumably ER lumen protein, can regulate cytosolic effectors of apoptosis is not known. Here we provide evidence that a subpopulation of GRP78 can exist as an ER transmembrane protein, as well as co-localize with caspase-7, as confirmed by fluorescence microscopy. Co-immunoprecipitation studies further reveal endogenous GRP78 constitutively associates with procaspase-7 but not with procaspase-3. Lastly, a GRP78 mutant deleted of its ATP binding domain fails to bind procaspase-7 and loses its protective effect against etoposide-induced apoptosis.