Stress induction of GRP78/BiP and its role in cancer

GRP78, also referred to as BiP, is a central regulator of endoplasmic reticulum (ER) function due to its roles in protein folding and assembly, targeting misfolded protein for degradation, ER Ca(2+)-binding and controlling the activation of trans-membrane ER stress sensors. Further, due to its anti-apoptotic property, stress induction of GRP78 represents an important pro-survival component of the unfolded protein response. GRP78 is induced in a wide variety of cancer cells and cancer biopsy tissues. Recent progress, utilizing overexpression and siRNA approaches, establishes that GRP78 contributes to tumor growth and confers drug resistance to cancer cells. The discovery of GRP78 expression on the cell surface of cancer cells further leads to the development of new therapeutic approaches targeted against cancer, in particular, hypoxic tumors where GRP78 is highly induced. Progress has also been made in understanding how Grp78 is induced by ER stress. The identification of the transcription factors interacting with the ER stress response element leads to the discovery of multiple pathways whereby mammalian cells can sense ER stress and trigger the transcription of Grp78. In addition, advances have been made in understanding how Grp78 expression is regulated in the context of chromatin modification. This review summarizes the transcriptional regulation of Grp78, the molecular basis for the cytoprotective function of GRP78 and its role in cancer progression, drug resistance and potential future cancer therapy.