The Molecular Chaperone GRP78/BiP in the Development of Chemoresistance: Mechanism and Possible Treatment

Abstract

Treatment of several types of cancer such as lung, breast, prostate, and pancreas has shown notable progresses in the past decades. However, after an initial response, tumors eventually became resistant to chemotherapy. This phenomenon, known as chemoresistance, accounts for the death of most cancer patients. Several studies in patients refractory to therapy have revealed the upregulation of the molecular chaperone GRP78/Binding Protein, BiP (BiP) both at the RNA and protein expression level. Furthermore GRP78/BiP relocates to the cell membrane in malignant but not in benign cells. In this communication we review studies on the role and the mechanism of action of GRP78/BiP during development of chemoresistance in cancer cells. In addition we discuss the possible role of GRP78 as a biomarker and as a target in cancer therapy.

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

“…Some studies suggest that GRP78 membrane localization contributes to pro‐proliferative pathways (Lee, 2014; Roller and Maddalo, 2013). While GRP78 membrane localization is a novel and interesting concept in cancer biology, our study finds that chemoresistance in pancreatic cancer cells can be mediated by an overexpression and increased activity of ABC transporter genes.…”

“…To survive the pressure created by the tumor microenvironment, including hypoxia and nutrient deprivation, tumor cells utilize the UPR pathways (Avril et al ., 2017; Chevet et al ., 2015; Lee, 2007; Ma and Hendershot, 2004). Multiple components of the UPR have been linked to advanced tumor stage and chemoresistance in cancer (Lee, 2014; Roller and Maddalo, 2013; Shen et al ., 2017; Wang and Kaufman, 2014). For example, overexpression of PDIA5 in chronic myeloid leukemia shows increased resistance to imatinib (Chevet et al ., 2015).…”

“…GRP78, the regulator of the UPR, has previously been correlated with poor patient prognosis in multiple cancers, including pancreatic cancer (Avril et al ., 2017; Gifford et al ., 2016; Ma and Hendershot, 2004; Niu et al ., 2015; Wang and Kaufman, 2014). Based on correlation studies and direct overexpression leading to chemoresistance, numerous proteins in the UPR pathway have been targeted with small molecules in hopes to attenuate chemoresistance (Chevet et al ., 2015; Gifford et al ., 2016; Lee, 2014; Roller and Maddalo, 2013). In spite of a generous body of literature correlating chemoresistance to expression of genes involved in UPR, there have been almost no studies to elucidate the mechanism(s) by which UPR contributes to chemoresistance.…”

A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib

“…It has been identified in numerous organisms from yeast to humans (1)(2)(3)(4). The expression of GRP78 clearly increases during ER stress, and therefore is used as an ER stress marker (4). In addition, GRP78 is involved in the integrity and the regulation of the ER, and it prevents the aggregation of misfolded proteins, including apoB100, by targeting them to the degradation by the 26S proteasome (5).…”

“…GRP78 has critical roles in protein homeostasis and the unfolded protein response. It has been identified in numerous organisms from yeast to humans (1)(2)(3)(4). The expression of GRP78 clearly increases during ER stress, and therefore is used as an ER stress marker (4).…”