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Review
. 2023 Aug 21;29(1):112.
doi: 10.1186/s10020-023-00706-6.

Unveiling the dark side of glucose-regulated protein 78 (GRP78) in cancers and other human pathology: a systematic review

Amos Olalekan Akinyemi  1 , Kendall Elizabeth Simpson  1 , Sunday Faith Oyelere  2 , Maria Nur  1 , Chrispus Mutuku Ngule  1 , Bolaji Charles Dayo Owoyemi  3 , Vivian Adiila Ayarick  1 , Felix Femi Oyelami  1 , Oluwafunminiyi Obaleye  1 , Dave-Preston Esoe  1 , Xiaoqi Liu  1   4 , Zhiguo Li  5
Affiliations
Review

Unveiling the dark side of glucose-regulated protein 78 (GRP78) in cancers and other human pathology: a systematic review

Amos Olalekan Akinyemi et al. Mol Med. .

Abstract

Glucose-Regulated Protein 78 (GRP78) is a chaperone protein that is predominantly expressed in the lumen of the endoplasmic reticulum. GRP78 plays a crucial role in protein folding by assisting in the assembly of misfolded proteins. Under cellular stress conditions, GRP78 can translocate to the cell surface (csGRP78) were it interacts with different ligands to initiate various intracellular pathways. The expression of csGRP78 has been associated with tumor initiation and progression of multiple cancer types. This review provides a comprehensive analysis of the existing evidence on the roles of GRP78 in various types of cancer and other human pathology. Additionally, the review discusses the current understanding of the mechanisms underlying GRP78's involvement in tumorigenesis and cancer advancement. Furthermore, we highlight recent innovative approaches employed in downregulating GRP78 expression in cancers as a potential therapeutic target.

Keywords: BiP; Cancer; Chaperon; Disease; ER stress; ERAD; GRP78; URP.

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Conflict of interest statement

The authors state that they have no known conflicts of interest, whether financial or personal, that could have influenced the work presented in this paper.

Figures

Fig. 1
Fig. 1
Illustration of the inactive state of GRP78 and the presence of stress response elements (ERES) positioned upstream of the TATA element. In cells that are not experiencing stress, the ERES region is bound by NFY, SP1, and HDAC1, leading to the maintenance of low transcription levels for GRP78. Additionally, GRP78, located within the lumen of the endoplasmic reticulum (ER), interacts with the ER stress sensors (IRE1, ATF6, and PERK) and acts as a signaling component for the unfolded protein response (UPR)
Fig. 2
Fig. 2
Representation of the general mechanism by which GRP78 functions within the endoplasmic reticulum (ER). GRP78 plays a crucial role in assisting ER proteins by promoting their stability and facilitating the process of protein folding. This is achieved through its interaction with misfolded proteins and unassembled complexes, thereby initiating the ER-associated degradation (ERAD) pathway. Within this pathway, GRP78 targets the misfolded proteins for degradation through a series of events that involve ubiquitination and subsequent proteasomal degradation
Fig. 3
Fig. 3
A proposed comprehensive pathway illustrating the involvement of GRP78 as a central regulator in the cellular response to endoplasmic reticulum (ER) stress, known as the unfolded protein response (UPR). In this pathway, GRP78 acts as a master regulator, coordinating the UPR signaling cascade
Fig. 4
Fig. 4
A breakdown of cell surface GRP78 (csGRP78) roles in AKT/P13K/ mTOR pathway. AKT and phosphoinositide-dependent kinase-1 (PDK1) are both drawn to the membrane after PI3K produces the second messenger PIP3. Due to proximity, PDK1 can phosphorylate AKT at position T308 of the activation loop (T-loop). The rapamycin-resistant mTOR complex 2 then phosphorylates AKT at residue S473 of the hydrophobic motif (mTORC2), a key step in the complete activation of AKT's kinase activity. TSC2, a negative regulator of mTORC1 activity, is one of several additional substrates that AKT itself has the ability to phosphorylate
Fig. 5
Fig. 5
Diagrammatical Illustration showing multifactorial implications of GRP78 in various diseases
Fig. 6
Fig. 6
Overview of Synthetic and Natural Products that has been employed in Downregulating GRP78 in various cancers. Natural and synthetic compounds with anticancer properties that suppress GRP78 induction has been reported below; however, they exert pleiotropic effects
Fig. 7
Fig. 7
Depicts some significant agents that specifically target GRP78 on cell surface
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