Abstract SY44-01: Critical role of stress chaperone GRP78/BiP in cancer

Abstract

Abstract ER stress triggers an adaptive protein quality control mechanism, the unfolded protein response, that aims at restoring ER homeostasis by activating a cascade of signaling molecules to transiently arrest translation, to induce ER chaperones and enzymes to enhance the protein folding capacity, and to initiate a process to export and degrade the ER misfolded proteins (1). The most abundant and well-characterized ER chaperone is a 78 kilodalton glucose regulated protein, GRP78, also referred to as BiP. GRP78 is a multi-functional protein that can impact cancer and a wide range of human diseases via diverse mechanisms (2, 3). While traditionally GRP78 is regarded as a lumen ER protein playing a major role in protein processing and regulation of the activation of the ER stress transducers, it is now established that in specific cell types or when subjected to stress, GRP78 can be translocated to compartments outside the ER, including the cell surface, the cytosol, the mitochondria and the nucleus, and it can even be secreted, where it binds novel interacting partners and exerts new functions in cell growth, signaling and viability (4). GRP78 is overexpressed in a wide variety of human cancers and is commonly associated with poor prognosis and resistance to a wide range of anti-treatments including cytotoxic, anti-hormonal, DNA damaging, anti-angiogenesis and chromatin modifying, as well as radiation therapy (1, 3). In functional studies performed in cancer cell lines as well as in mouse models where GRP78 is conditionally knockdown in various tissues and organs, GRP78 is found to regulate tumor cell proliferation, apoptosis, autophagy, angiogenesis, invasion and metastasis, inflammation and immunity as well as stem cell self renewal. The pro-survival effects of GRP78 in cancer are observed in cancer cells as well as tumor associated endothelial cells and involve not only the ER form of GRP78 but GRP78 in other cellular locations, in particular GRP78 on the cell surface. As GRP78 is a critical factor in tumor initiation, progression, metastasis and therapeutic resistance, it is an attractive target for therapeutic intervention. The recent discovery that GRP78 is preferably expressed on the surface of tumor cells in vivo enables specific tumor targeting with minimal harmful effects on normal cells. As cell surface GRP78 expression is further detected in some tumor initiating cells and increased in metastasized and resistant tumors and in hypoxic endothelial cells supporting tumor growth, cytotoxic agents against cell surface GRP78 has the potential to target these in addition to the primary tumor. An oncogenic function of GRP78 has been attributed to the activation of the phosphoinositide (PI3K) pathway (4). Recently, a novel anti-GRP78 monoclonal antibody has been identified that modulates the PI3K pathway without compensatory MAPK pathway activation. It is capable of halting or reversing tumor progression in various spontaneous tumor models mimicking genetic knockdown of GPR78, and inhibiting human cancer growth and metastasis in xenograft models. The humanized form of this antibody retains its GRP78 binding affinity and efficacy, and is non-toxic to normal organs. These and other advances suggest targeting GRP78 holds promise as a novel approach to combat cancer progression and recurrence.