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

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical resection when these tumours are detected at an early stage, this cancer is usually asymptomatic, and disease only becomes apparent after metastasis. Several risk factors are associated with this disease, the most relevant being chronic pancreatitis, diabetes, tobacco and alcohol intake, cadmium, arsenic and lead exposure, certain infectious diseases, and the mutational status of some genes associated to a familial component. PDAC incidence has increased in recent decades, and there are few alternatives for chemotherapeutic treatment. Endoplasmic reticulum (ER) stress factors such as GRP78/BiP (78 kDa glucose-regulated protein), ATF6α (activating transcription factor 6 isoform α), IRE1α (inositol-requiring enzyme 1 isoform α), and PERK (protein kinase RNA-like endoplasmic reticulum kinase) activate the transcription of several genes involved in both survival and apoptosis. Some of these factors aid in inducing a non-proliferative state in cancer called dormancy. Modulation of endoplasmic reticulum stress could induce dormancy of tumour cells, thus prolonging patient survival. In this systematic review, we have compiled relevant results concerning those endoplasmic reticulum stress factors involved in PDAC, and we have analysed the mechanism of dormancy associated to endoplasmic reticulum stress and its potential use as a chemotherapeutic target against PDAC.

Keywords: ATF4; ATF6α; ER stress; GRP78; IRE1α; P38; PERK; UPR; dormancy; pancreatic ductal adenocarcinoma.

Figure 1

Consequences of endoplasmic reticulum stress response pathway. Unfolded protein accumulation and other stress conditions such as hypoglycemia and hypoxia cause the unbinding of GRP78 from ATF6α, PERK, and IRE1. These three factors activate different signalling pathways that lead to survival or to apoptosis. UP: Unfolded proteins; ER: Endoplasmic reticulum; ERSR: Endoplasmic reticulum stress response; VEGF: vascular endothelial growth factor; AKT: AKT serine/threonine kinase; ATF4: activating transcription factor 4; CHOP: CCAAT/enhancer binding protein (C/EBP)-homologous protein; JNK: c-Jun N-terminal kinase; EIF2: eukaryotic initiation factor 2; XBP1: transcription factor X-box 1.