GRP78 and next generation cancer hallmarks: An underexplored molecular target in cancer chemoprevention research

Highlights

• GRP78 overexpression is reported in various cancers.

• Emerging hall marks of cancer includes metabolic reprogramming and immune evasion.

• Increased GRP78 influence energy metabolism and immune evasion.

• Crosstalk might exist between GRP78-tumor glycolysis-immune evasion.

• Very few natural products have been investigated as GRP78 modulators.

Abstract

Glucose regulated protein 78 (GRP 78), a master regulator of endoplasmic reticulum stress has been reported to be up regulated in various cancers and remains a crucial link between tumor glycolysis and tumor microenvironment. Overexpressed GRP78 has also shown to induce immune suppressive molecules and thereby tumor immune evasion. On the other hand emerging reports indicates that the next generation hallmarks viz., metabolic reprogramming and immune evasion, the two distinct processes are suggested to be fundamentally linked which is yet to be explored. Our concern is, if GRP78 is considered as a connecting link between these two different processes then targeting this triangle would be a promising approach in anticancer drug discovery. Lack of sufficient literature on this aspect represents GRP78 as an under explored target in anti-cancer research. The objective of this review is to provide a concise and integrated information on GRP78 and its association with tumor glycolysis and immune evasion which will revive and draw attention of the researchers to consider GRP78 as a potential drug target for cancer intervention and it also highlights few potential natural products investigated so far as GRP78 inhibitors.

Introduction

Being a largest intracellular compartment of eukaryotic cells, endoplasmic reticulum (ER) plays a unique role in protein secretion, protein folding and also targeting protein to its respective destination through Golgi complex. ER is an assembly site for newly-synthesized polypeptides and multimeric proteins to acquire proper folding and glycoproteins acquire their asparagine-linked glycans. ER also acts as a site for quality control where regardless of size and post-translational modifications, the folding states of all proteins must be identified as unfolded, properly folded, or terminally misfolded and accordingly processed for folding, precise folding, export and maturation, or retro translocation to the cytosol for degradation [1]. In terms of protein conformation in vivo, it is important to note that cellular processes such as protein synthesis, transport and response to stress necessitates proper protein folding [2]. The cellular chaperone machinery ensures that folding is efficient for most proteins [3]. Glucose regulated proteins (GRPs) are molecular chaperones that performs critical functions in ER.

Stressful conditions like nutrient starvation, hypoxia, and disturbance in intracellular Ca²⁺ ions, low pH, reactive oxygen species (ROS) accumulation, proinflammatory signals and proliferative signals could induce protein aggregation and misfolding in the ER. ER stress triggers an evolutionarily conserved response called the unfolded protein response (UPR) that lead to the transcription of grp genes to many fold. There are several types of GRPs including GRP78, GRP94, GRP170, ERp72, PDI, calreticulin and GRP58 (alias ERp57) all of them are ER molecular chaperones that assist in protein folding and assembly [4]. Among all, the 78 kDa GRP (GRP78) also referred to as ’immunoglobulin heavy chain-binding protein’ (BiP), is one of the best-characterized endoplasmic reticulum (ER) chaperone protein facilitating the unfolded protein response (UPR). The mechanism of GRP78 in initiating UPR and it regulation is reviewed in detailed earlier by Hetz [5]. Emerging evidences explored the critical role played by GRP78 in carcinogenesis with respect to cancer progression, malignancy, and drug resistance [[6], [7], [8], [9]]. But lack of sufficient literature represents that GRP78 remains an under explored target in anti-cancer research though its function and localization are well investigated. On the other hand the next generation hallmarks viz., metabolic reprogramming i.e the ability of cancer cells to exploit various metabolic pathways for energy production and immune evasion i.e cancer cell’s ability to escape immune surveillance are considered as two distinct processes. Emerging reports indicate that these two processes might be fundamentally linked in cancer progression. This raises a concern that whether GRP78 might be that link connecting the two different targets to form a triangle of GRP78-metabolic reprogramming-immune evasion? To address this concern the interaction between GRP78-tumor glycolysis-immune evasion are reviewed to revive interests in researchers to investigate this domain in detail.