Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis

Abstract

Cancer constitutes a grave problem nowadays in view of the fact that it has become one of the main causes of death worldwide. Poor clinical prognosis is presumably due to cancer cells metabolism as tumor microenvironment is affected by oxidative stress. This event triggers adequate cellular response and thereby creates appropriate conditions for further cancer progression. Endoplasmic reticulum (ER) stress occurs when the balance between an ability of the ER to fold and transfer proteins and the degradation of the misfolded ones become distorted. Since ER is an organelle relatively sensitive to oxidative damage, aforementioned conditions swiftly cause the activation of the unfolded protein response (UPR) signaling pathway. The output of the UPR, depending on numerous factors, may vary and switch between the pro-survival and the pro-apoptotic branch, and hence it displays opposing effects in deciding the fate of the cancer cell. The role of UPR-related proteins in tumorigenesis, such as binding the immunoglobulin protein (BiP) and inositol-requiring enzyme-1α (IRE1α), activating transcription factor 6 (ATF6) or the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), has already been specifically described so far. Nevertheless, due to the paradoxical outcomes of the UPR activation as well as gaps in current knowledge, it still needs to be further investigated. Herein we would like to elicit the actual link between neoplastic diseases and the UPR signaling pathway, considering its major branches and discussing its potential use in the development of a novel, anti-cancer, targeted therapy.

Keywords: apoptosis; cancer; cancer treatment; carcinogenesis; endoplasmic reticulum stress; protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK); reactive oxygen species; unfolded protein response.

Figure 1

Dual response to Endoplasmic Reticulum (ER) stress conditions in normal epithelial cells and cancer cells via the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-dependent Unfolded Protein Response (UPR) signaling pathway activation. Numerous stress-inducing factors may contribute to impaired formation of proteins and their subsequent accumulation, resulting in activation of UPR signaling pathway in both cell types. While in normal cells their origin is mainly extracellular and rather occasional, cancer cells are shown to be permanently exposed to self-induced, chronic stressors as an effect of their own metabolism. This is the reason why they developed adaptive mechanisms to deal with severe stress conditions and avoid apoptosis, which results in a positive feedback loop. The PERK/eukaryotic translation initiation factor 2α/activating transcription factor 4 (PERK-eIF2α-ATF4) axis is certainly involved in both pro-survival and pro-apoptotic signaling pathways.

Figure 2

Three major branches of the Unfolded Protein Response (UPR) signaling pathway and their interconnections. Under endoplasmic reticulum (ER) stress conditions, damaged proteins accumulate within the ER lumen and bind to binding immunoglobulin proteins (BiPs), which in turn dissociate from transmembrane complexes with activating transcription factor 6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) in attempt to refold the proteins. As a result, three branches of the UPR become activated and trigger adequate stress responses. ATF6, after cleavage in Golgi apparatus, enters the nucleus to activate cytoprotective genes. It also upregulates X-box binding protein 1 (XBP1) mRNA, which is subsequently spliced by IRE1α to enhance the pro-survival effect. The main downstream target of PERK, eukaryotic translation initiation factor 2α (eIF2α), inhibits the global protein synthesis, with the exclusive translation of specific mRNAs such as activating transcription factor 4 (ATF4). Both nuclear factor-like 2 (Nrf2) and forkhead box protein O1 (FOXO) proteins, directly phosphorylated by PERK, are responsible for antioxidant and cell survival mechanisms. Additionally, PERK may act on FOXO indirectly via phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) signaling pathway. Apoptosis may be induced either by IRE1α, via c-Jun N-terminal kinases (JNKs) signaling pathway, or by PERK-mediated C/EBP homologous protein transcription factor (CHOP).

Figure 3

Biological origin of free radicals and their effect on cell viability. Reactive Oxygen Species (ROS) are generally derived both from intrinsic factors (enzymatic reactions physiologically conducted in subcellular organelles) and from the numerous extrinsic ones. Although ROS evidently remain essential for normal functioning of the cell, including immune response or redox signaling, their overload may prove harmful and cause significant damage. Ultimately, it may lead to execution of apoptotic or necrotic cell death or even drive tumor growth. Unfolded Protein Response (UPR) signaling pathway is closely linked to ROS-induced oxidative stress and it becomes activated to address cellular redox imbalance.