GRP78=BiP is a major endoplasmic reticulum (ER) chaperone protein critical for protein quality control of the ER, as well as controlling the activation of the ER-transmembrane signaling molecules. Through creation of mouse models targeting the Grp78 allele, the function of GRP78 in development and disease has been investigated. These led to the discovery that GRP78 function is obligatory for early embryonic development. However, in adult animals, GRP78 is preferably required for cancer cell survival under pathologic conditions such as tumor progression and drug resistance. The discovery of surface localization of GRP78 in cancer cells reveals potential novel function, interaction with cell-surface receptors, and possible therapeutic implications. Mouse models also reveal that GRP78 controls maturation and secretion of neuronal factors for proper neural migration and offers neuroprotection. Antioxid. Redox Signal. 11, 2307-2316.

The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity. [Cancer Res 2008; 68(2):498-505]

Almost 20 years have passed since the first laboratory evidence emerged that an abundant message encoding a protein with homology to the C1q superfamily is highly specifically expressed in adipocytes. At this stage, we refer to this protein as adiponectin. Despite more than 10,000 reports in the literature since its initial description, we seem to have written only the first chapter in the textbook on adiponectin physiology. With every new aspect we learn about adiponectin, a host of new questions arise with respect to the underlying molecular mechanisms. Here, we aim to summarize recent findings in the field and bring the rodent studies that suggest a causal relationship between adiponectin levels in plasma and systemic insulin sensitivity in perspective with the currently available data on the clinical side.

GRP78/BiP has recently emerged as a novel biomarker for aggressive prostate cancer. Here, we report that homozygous deletion of Grp78 specifically in mouse prostate epithelium suppresses prostate tumorigenesis without affecting postnatal prostate development and growth. Mouse prostates with double conditional knockout of Grp78 and Pten exhibit normal histology and cytology, in contrast to the invasive adenocarcinoma in mouse prostates with Pten inactivation. AKT activation in Pten null prostate epithelium is inhibited by Grp78 homozygous deletion, corresponding with suppression of AKT phosphorylation by GRP78 knockdown in prostate cancer cell line. Thus, inactivation of GRP78 may represent a previously undescribed approach to stop prostate cancer and potentially other cancers resulting from the loss of PTEN tumor suppression and/or activation of the oncogenic AKT.cancer suppressor ͉ chaperone gene ͉ inactivation P rostate cancer is the most common cancer in men and develops through successive stages including prostatic intraepithelial neoplasia (PIN), carcinoma in situ, invasive adenocarcinoma, and metastatic disease. Although local surgery, radiation, or hormonal ablation provide initial response at early stages of the disease, tumor cells often develop resistance and relapse. Thus, the identification of new therapeutic targets for prostate cancer is of critical importance. The 78-kDa glucose regulated protein (GRP78) was initially linked to prostate cancer progression and metastasis through epitope mapping of humoral immune response from cancer patients, and identified as a functional molecular target for circulating ligands (1). Recent studies further revealed that Ϸ2/3 of human prostate cancers expressed high level of GRP78, associating with recurrence, development of castration-resistance, and poor survival (2, 3). These studies provide the first hints that GRP78 may have a critical role in prostate cancer development and therapeutic resistance.GRP78, also referred to as BiP or HSPA5, is a member of the HSP70 protein family. As a major endoplasmic reticulum (ER) chaperone, GRP78 facilitates protein folding and assembly, protein quality control, ER-associated protein degradation, Ca 2ϩ binding, and regulation of transmembrane ER stress inducers (4, 5). GRP78 is encoded by a single copy gene in rodents and humans. It is expressed as early as at the 2-cell stage of embryonic development, and is essential for proliferation and survival of embryonic cells (6). GRP78 is highly induced in a wide range of tumors through intrinsic factors such as altered glucose metabolism of cancer cells, compounded by extrinsic factors such as glucose deprivation, hypoxia, and acidosis in the microenvironment of poorly-perfused solid tumor (7). In a wide variety of cancer cell lines and xenograft models, GRP78 has emerged as having a critical role in cancer cell survival, tumor progression, and resistance to therapy (7-10). Despite these advances, it remains unknown whether GRP78 could also be essential for the genesis of tumor. I...