An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.

Keywords: activating transcription factor 6 (ATF6); endoplasmic reticulum (ER); inositol-requiring enzyme 1 (IRE1); protein kinase RNA-like ER kinase (PERK); unfolded protein response (UPR).

Figure 1

The unfolded protein response. Accumulation of unfolded proteins within the ER lumen leads to the dissociation of GRP78 from three ER stress sensors IRE1, PERK and ATF6, and their subsequent activation.Activation of IRE1 results in the removal of a 26 nucleotide intron from XBP1u mRNA. RTCB acts to ligate the mRNA, and this product is translated into the transcription factor XBP1s. Additionally, activated IRE promotes regulated IRE1 dependent decay (RIDD). RIDD activity of IRE1 is responsible for the cleavage of a subset of RNAs/miRNAs. When ATF6 is activated, it is cleaved in the Golgi to form an active transcription factor ATF6N. Upon activation, PERK phosphorylates eIF2α, and this results in the attenuation of global translation. However, the transcription factor ATF4 is active, and it acts to upregulate a subset of genes. The transcriptional programme mediated by XBP1s, ATF4 and ATF6N promotes expression of chaperones, components of ER associated protein degradation (ERAD), increased ER capacity and reduced protein translation to ameliorate ER stress and restore homeostasis. Additionally, UPR-mediated gene expression also directly impact autophagy, cytokine production and apoptosis.

Figure 2

The Role of unfolded protein response (UPR) in pancreatic ductal adenocarcinoma (PDAC).Various stresses including environmental factors, the tumour microenvironment, oncogenesis, high secretory demand and metabolic reprogramming activate the UPR in pancreatic cancer. This results in upregulation of UPR gene targets. Many of these gene promote oncogenic pathways in PDAC cells. UPR activation promotes a pro-tumorigenic pancreatic stellate cell (PSCs) phenotype. Paracrine signalling from PDAC cells and PSCs, as a consequence of UPR activation in PDAC, also promotes tumorigenic behaviours.