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Unfolded Protein Response in Inflammation and Cancer

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 22257

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Special Issue Editor

Dr. Femke Heindryckx

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Guest Editor

Department of Medical Cell Biology, Uppsala University, 752 36 Uppsala, Sweden
Interests: liver cancer; fibrosis; endoplasmic reticulum stress; tumor–stroma interactions; inflammation-induced cancer

Special Issue Information

Dear Colleagues,

Endoplasmic reticulum (ER) stress and the activation of the unfolded protein response play an important role in the onset and progression of many inflammatory diseases. Inflammation is also considered a critical component of carcinogenesis, as many tumors occur in a natural environment of chronic inflammation, and tumor cells are known to modulate the inflammatory niche to create an environment that supports tumor growth. In addition, tumor cells continuously endure both oncogenic and environmental stresses, as malignant cells face increased demands for protein synthesis and adapt to grow in an oxygen- and nutrient-deprived environment. It is therefore not surprising that actors of the unfolded protein response have been implicated in nearly all types of cancer.

The physiological significance of ER stress in cancer and inflammation is currently a very active field of research; and targeting the different arms of the unfolded protein response has been shown to alter disease progression in several in vivo and in vitro models. The purpose of this Special Issue is to provide an overview of recent advances in this area, specifically by covering different angles of how ER stress can influence inflammation, cancer, and the combination of these two pathologies.

Dr. Femke Heindryckx
Guest Editor

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Keywords

unfolded protein response
endoplasmic reticulum stress
inflammation
cancer
stroma
fibrosis

Published Papers (6 papers)

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Research

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17 pages, 5461 KiB

Open AccessArticle

Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2

by Roberta Rinaldi, Rocchina Miglionico, Ilaria Nigro, Rosarita D’Orsi, Lucia Chiummiento, Maria Funicello, Paolo Lupattelli, Ilaria Laurenzana, Alessandro Sgambato, Magnus Monné, Faustino Bisaccia and Maria Francesca Armentano

Cells 2021, 10(11), 3052; https://doi.org/10.3390/cells10113052 - 06 Nov 2021

Cited by 3 | Viewed by 2090

Abstract

Background: Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. Methods: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. Results: RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. Conclusions: These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates. Full article

(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)

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16 pages, 1227 KiB

Open AccessArticle

Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation

by James Moore, Ivan Osinnii, Amandine Grimm, Björn Oettinghaus, Anne Eckert, Stephan Frank and Erik C. Böttger

Cells 2021, 10(11), 2856; https://doi.org/10.3390/cells10112856 - 23 Oct 2021

Cited by 2 | Viewed by 2698

Abstract

Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of stress granules. Together, our results point to a concerted response to error-prone translation to alleviate ER stress in favor of activating alternative proteostasis mechanisms, most likely to avoid cell damage and apoptotic pathways, which would result from persistent activation of the ER and integrated stress responses. Full article

(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)

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20 pages, 5061 KiB

Open AccessArticle

Anthracyclins Increase PUFAs: Potential Implications in ER Stress and Cell Death

by David Balgoma, Fredrik Kullenberg, Carlemi Calitz, Maria Kopsida, Femke Heindryckx, Hans Lennernäs and Mikael Hedeland

Cells 2021, 10(5), 1163; https://doi.org/10.3390/cells10051163 - 11 May 2021

Cited by 12 | Viewed by 3963

Abstract

Metabolic and personalized interventions in cancer treatment require a better understanding of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes in the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethanolamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggest supplementation with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depending on the type of tumor and the individual. Finally, in agreement with previous research, we found a relationship across the different cell types between: (i) the change in endoplasmic reticulum (ER) stress, and (ii) the imbalance between PUFAs and cholesterol and saturated lipids. In the light of previous research, this imbalance partially explains the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies. Full article

(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)

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15 pages, 2983 KiB

Open AccessArticle

Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism

by Domenico Conza, Paola Mirra, Gaetano Calì, Luigi Insabato, Francesca Fiory, Francesco Beguinot and Luca Ulianich

Cells 2021, 10(5), 1067; https://doi.org/10.3390/cells10051067 - 30 Apr 2021

Cited by 12 | Viewed by 3062

Abstract

Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer. Full article

(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)

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Review

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19 pages, 2266 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

by Jaafar Khaled, Maria Kopsida, Hans Lennernäs and Femke Heindryckx

Cells 2022, 11(4), 632; https://doi.org/10.3390/cells11040632 - 11 Feb 2022

Cited by 30 | Viewed by 4935

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC. Full article

(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)

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20 pages, 1268 KiB

Open AccessReview

AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus

by Marisa Passarelli and Ubiratan Fabres Fabres Machado

Cells 2022, 11(1), 104; https://doi.org/10.3390/cells11010104 - 29 Dec 2021

Cited by 16 | Viewed by 4574

Abstract

In recent decades, complex and exquisite pathways involved in the endoplasmic reticulum (ER) and inflammatory stress responses have been demonstrated to participate in the development and progression of numerous diseases, among them diabetes mellitus (DM). In those pathways, several players participate in both, reflecting a complicated interplay between ER and inflammatory stress. In DM, ER and inflammatory stress are involved in both the pathogenesis of the loss of glycemic control and the development of degenerative complications. Furthermore, hyperglycemia increases the generation of advanced glycation end products (AGEs), which in turn refeed ER and inflammatory stress, contributing to worsening glycemic homeostasis and to accelerating the development of DM complications. In this review, we present the current knowledge regarding AGEs-induced and ER/inflammation-mediated regulation of the expression of GLUT4 (solute carrier family 2, facilitated glucose transporter member 4), as a marker of glycemic homeostasis and of cardiovascular disease (CVD) development/progression, as a leading cause of morbidity and mortality in DM. Full article

(This article belongs to the Special Issue Unfolded Protein Response in Inflammation and Cancer)

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