Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

Abstract

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.

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…Although homozygous knockout of Grp78 results in embryonic lethality, heterozygous Grp78 mice expressing an ∼50% level of GRP78 are viable and phenotypically normal (20). The creation of targeted heterozygous knockout of Grp78 in various organs revealed that although it has a minimal effect on organ development and function, it exerts a profound suppressive effect in both solid and blood tumors notably driven by loss of the Pten tumor suppressor gene (14,21,22). Despite these advances, the mechanistic involvement of GRP78 in oncogenic mutant KRASdriven cancers is just emerging.…”

“…cancer cells represents a major prosurvival response, suppressing apoptosis while promoting proliferation and invasiveness (14). Recently, it was discovered that ER stress can actively promote cell-surface localization of GRP78 (15), where it assumes coreceptor functions with cell-surface protein partners in regulating signal transduction pathways, including PI3K/AKT/S6 activation (16)(17)(18)(19).…”

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.…”