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

Abstract

Chemoresistance is a major therapeutic challenge that plays a role in the poor statistical outcomes in pancreatic cancer. Unfolded protein response (UPR) is one of the homeostasis mechanisms in cancer cells that have been correlated with chemoresistance in a number of cancers including pancreatic cancer. In this study, we show that modulating glucose regulatory protein 78 (GRP78), the master regulator of the UPR, can have a profound effect on multiple pathways that mediate chemoresistance. Our study showed for the first time that silencing GRP78 can diminish efflux activity of ATP‐binding cassette (ABC) transporters, and it can decrease the antioxidant response resulting in an accumulation of reactive oxygen species (ROS). We also show that these effects can be mediated by the activity of specificity protein 1 (SP1), a transcription factor overexpressed in pancreatic cancer. Thus, inhibition of SP1 negatively affects the UPR, deregulates the antioxidant response of NRF2, as well as ABC transporter activity by inhibiting GRP78‐mediated ER homeostasis. Sp1 and NRF2 have been classified as nononcogene addiction genes and thus are imperative to understanding the molecular mechanism of resistance. These finding have huge clinical relevance as both Sp1 and GRP78 are overexpressed in pancreatic cancer patients and increased expression of these proteins is indicative of poor prognosis. Understanding how these proteins may regulate chemoresistance phenotype of this aggressive cancer may pave the way for development of efficacious therapy for this devastating disease.

Identification of Novel Biomarkers in Pancreatic Tumor Tissue to Predict Response to Neoadjuvant Chemotherapy

“…The top four biomarkers for NAC resistance, namely, GRP78, CADM1, PGES2, and RUXF demonstrated very high predictive ability for chemo-resistance with AUROC > 0.92. Notably, GRP78 has been previously demonstrated to play an important role in mediating chemoresistance in PDAC (15)(16)(17). Moreover, RUXF and PGES2 are known to be involved in chemo-resistance in ovarian and colorectal cancer, respectively (18,19).…”

Targeted inhibition of GRP78 by HA15 promotes apoptosis of lung cancer cells accompanied by ER stress and autophagy

“…It has been reported that high expression of GRP78 could promote tumorigenesis and drug resistance, and inhibition of GRP78 could improve the efficacy of chemotherapy drugs ( Huang et al, 2016 ; Dauer et al, 2018 ; Cook and Clarke, 2015 ). A clinical study, including 163 peripheral blood samples from non-small-cell lung cancer patients, revealed that GRP78 is highly enriched in advanced stages, significantly higher than seen in early-stage patients, which may be important in the carcinogenesis of non-small-cell lung cancer, and is associated with a poor prognosis ( Ma et al, 2015 ).…”

New Hope for Pancreatic Ductal Adenocarcinoma Treatment Targeting Endoplasmic Reticulum Stress Response: A Systematic Review

“…GRP78 downregulation with siRNAs in combination with chemotherapeutics increased cell death compared to treatment or individual silencing. GRP78 downregulation also decreased ABC transporter activity, sensitising the PDAC cells to several chemotherapeutic agents [ 59 ]. GRP78 overexpression contributed to tumour angiogenesis independently of vascular endothelial growth factor (VEGF) and it increased AKT phosphorylation and ERK1/2 activation [ 60 ].…”