Special Issue "Therapeutic Targeting of the Unfolded Protein Response in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 December 2019.

Special Issue Editor

Dr. Eric Chevet
E-Mail Website1 Website2
Guest Editor
INSERM U1242, University of Rennes, Rennes, France
Interests: endoplasmic reticulum; proteostasis; unfolded protein response; cancer; PERK; IRE1; ATF6; therapeutic approach

Special Issue Information

Dear Colleagues,

In recent years, endoplasmic reticulum (ER) proteostasis has been identified as a major player in cancer. In particular, the signaling mechanisms that are involved in ER proteostasis maintenance were shown to significantly contribute to cancer hallmarks such as epithelial-to-mesenchymal transition (EMT), inflammation, migration/invasion, or resistance to therapy. These signaling mechanisms are collectively assembled under the name of unfolded protein response (UPR) and transduced by three ER resident proteins named IRE1, PERK, and ATF6. The role of IRE1 and PERK in cancer development and their relevance as therapeutic targets in the disease have clearly been documented, whereas the role of ATF6 in oncogenesis or treatment resistance remains less clear.

In the past five years, a large number of pharmacological or genetic approaches targeting the three arms of the UPR were developed to be applied as therapeutics in various diseases, including cancer.

In this Special Issue, we aim at providing (i) state-of-the-art reviews on the current knowledge regarding the pharmacological and genetic tools that were developed to selectively target ATF6, PERK, IRE1 or UPR regulators, as well as their reported utilizations in cancer models; (ii) research articles describing novel pharmacological molecules or genetic tools targeting IRE1, PERK, ATF6 or any other UPR regulators, as well as their potential use in cancer models; and finally, (iii) novel preclinical results with UPR targeting drugs.

Dr. Eric Chevet
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (3 papers)

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Research

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Open AccessArticle
The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation
Cancers 2019, 11(12), 1921; https://doi.org/10.3390/cancers11121921 - 02 Dec 2019
Abstract
Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the [...] Read more.
Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Unfolded Protein Response in Cancer)

Review

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Open AccessReview
Proteostasis in the Endoplasmic Reticulum: Road to Cure
Cancers 2019, 11(11), 1793; https://doi.org/10.3390/cancers11111793 - 14 Nov 2019
Abstract
The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in [...] Read more.
The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in the folding capacity of the ER caused by a large variety of pathophysiological insults leads to the accumulation of unfolded or misfolded proteins in this organelle, known as ER stress. Upon ER stress, unfolded protein response (UPR) of the ER is activated, integrates ER stress signals, and transduces the integrated signals to relive ER stress, thereby leading to the re-establishment of proteostasis. Intriguingly, severe and persistent ER stress and the subsequently sustained unfolded protein response (UPR) are closely associated with tumor development, angiogenesis, aggressiveness, immunosuppression, and therapeutic response of cancer. Additionally, the UPR interconnects various processes in and around the tumor microenvironment. Therefore, it has begun to be delineated that pharmacologically and genetically manipulating strategies directed to target the UPR of the ER might exhibit positive clinical outcome in cancer. In the present review, we summarize recent advances in our understanding of the UPR of the ER and the UPR of the ER–mitochondria interconnection. We also highlight new insights into how the UPR of the ER in response to pathophysiological perturbations is implicated in the pathogenesis of cancer. We provide the concept to target the UPR of the ER, eventually discussing the potential of therapeutic interventions for targeting the UPR of the ER for cancer treatment. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Unfolded Protein Response in Cancer)
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Open AccessReview
Leveraging the Role of the Metastatic Associated Protein Anterior Gradient Homologue 2 in Unfolded Protein Degradation: A Novel Therapeutic Biomarker for Cancer
Cancers 2019, 11(7), 890; https://doi.org/10.3390/cancers11070890 - 26 Jun 2019
Abstract
Effective diagnostic, prognostic and therapeutic biomarkers can help in tracking disease progress, predict patients’ survival, and considerably affect the drive for successful clinical management. The present review aims to determine how the metastatic-linked protein anterior gradient homologue 2 (AGR2) operates to affect cancer [...] Read more.
Effective diagnostic, prognostic and therapeutic biomarkers can help in tracking disease progress, predict patients’ survival, and considerably affect the drive for successful clinical management. The present review aims to determine how the metastatic-linked protein anterior gradient homologue 2 (AGR2) operates to affect cancer progression, and to identify associated potential diagnostic, prognostic and therapeutic biomarkers, particularly in central nervous system (CNS) tumors. Studies that show a high expression level of AGR2, and associate the protein expression with the resilience to chemotherapeutic treatments or with poor cancer survival, are reported. The primary protein structures of the seven variants of AGR2, including their functional domains, are summarized. Based on experiments in various biological models, this review shows an orchestra of multiple molecules that regulate AGR2 expression, including a feedback loop with p53. The AGR2-associated molecular functions and pathways including genomic integrity, proliferation, apoptosis, angiogenesis, adhesion, migration, stemness, and inflammation, are detailed. In addition, the mechanisms that can enable the rampant oncogenic effects of AGR2 are clarified. The different strategies used to therapeutically target AGR2-positive cancer cells are evaluated in light of the current evidence. Moreover, novel associated pathways and clinically relevant deregulated genes in AGR2 high CNS tumors are identified using a meta-analysis approach. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Unfolded Protein Response in Cancer)
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