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1. A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

Author

Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Timothy Langlais, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Eric Chevet, Leif A. Eriksson, Xavier Guillory, Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomedical Research Foundation of the Academy of Athens (BRFAA), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Gothenburg (GU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), We thank Dr Frédéric Delom, Dr Delphine Fessart, Pr Reynald Gillet, Dr David Gillot, Dr Élodie Lafont, Dr Eric Ogier-Denis, and Pr Afshin Samali for the critical reading of the manuscript. Part of this work was carried out using the Spectroscopies-CDTP core facility, the animal facility ARCHE, and the immunohistochemistry platform H2P2 (UMS Biosit, Université de Rennes 1- Campus de Villejean - 35043 RENNES Cedex, FRANCE). This work was supported by grants from Institut National du Cancer (INCa, PLBIO), Agence Nationale de la Recherche (ANR, ERAAT), Fondation pour la Recherche Médicale (FRM, DEQ20180339169), the EU COST action 861952 \'Proteocure\' and Cancéropôle Grand-Ouest (Gliotreat) to E.C., EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED) grants to E.C., A.C., and L.A.E., INSERM (International Research Project – TUPRIC) to A.C. and E.C., La Ligue contre le Cancer (comités 22, 35, 36, 56 et 85), INSERM, Région Bretagne and from the institut des Neurosciences Cliniques de Rennes (INCR) to T.A. The Swedish Research Council (VR, grant no 2019-3684)), the Swedish Cancer Foundation (grant no 21-1447 Pj) and the Swedish National Infrastructure for Computing (SNIC, funded in part through VR grant agreement 2018-05973) are gratefully acknowledged for funding and allocations of computing time, respectively (L.A.E.). D.P.R. was funded by grants from INSERM (LA VANNETAISE) and the Brittany Region, D.D. was funded by EU H2020 MSCA ITN-675448, C.S. was funded by a Plan Cancer post-doctoral fellowship, X.G. was funded by the Fondation ARC pour la recherche sur le cancer, grant PDF20191209830, C.S. was funded by a post-doctoral fellowship from INSERM-plan cancer., and ANR-17-RAR3-0003,ERAAT,Enhancing Endoplasmic Reticulum Proteostasis to Rescue Alpha1 Antitrypsin Deficiency(2017)

Subjects
Biological sciences, Multidisciplinary, Medicine, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Molecular neuroscience, Neuroscience
Abstract

International audience; Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood-brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB.

Published
2023
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3. A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice

Author

Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Eric Chevet, Leif A. Eriksson, and Xavier Guillory

Abstract

Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. We first characterized the candidates in vitro and in cellular models. We showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). From these inhibitors, we retained a Blood-Brain Barrier (BBB) permeable molecule (Z4P) and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB. We thus satisfy an unmet need for targeted, non-toxic, IRE1 inhibitors as adjuvant therapeutic agents against GB.

Published
2022
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4. Pharmacological Targeting of IRE1 in Cancer

Author

Dimitrios Doultsinos, Eric Chevet, Antonio Carlesso, Diana Pelizzari Raymundo, Xavier Guillory, Leif A. Eriksson, Jonchère, Laurent, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Gothenburg (GU), This work was funded by grants from Institut National du Cancer (INCa PLBIO), Fondation pour la Recherche Médicale (FRM, équipe labellisée 2018), ERANET , and Agence Nationale de la Recherche (ERAAT) to E.C., EU H2020 MSCA ITN-675448 (TRAINERS), and MSCA RISE-734749 (INSPIRED) provided grants to L.A.E. and E.C. D.P.R. was funded by INSERM (LA VANNETAISE). X.G. was funded by a post-doctoral fellowship from Fondation ARC , and D.D. and A.C. were MSCA ITN fellows (TRAINERS)., Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)

Subjects
0301 basic medicine, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), IRE1, Protein Serine-Threonine Kinases, Inositol-requiring enzyme 1, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Allosteric Regulation, Protein Domains, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Endoribonucleases, inhibitors, Humans, Medicine, Mode of action, Protein Kinase Inhibitors, activators, business.industry, Cancer, unfolded protein response, Endoplasmic Reticulum Stress, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, endoplasmic reticulum, 030104 developmental biology, Oncology, Protein kinase domain, 030220 oncology & carcinogenesis, Proteostasis, Unfolded protein response, business, Signal Transduction
Abstract

International audience; IRE1α (inositol requiring enzyme 1 alpha) is one of the main transducers of the unfolded protein response (UPR). IRE1α plays instrumental protumoral roles in several cancers, and high IRE1α activity has been associated with poorer prognoses. In this context, IRE1α has been identified as a potentially relevant therapeutic target. Pharmacological inhibition of IRE1α activity can be achieved by targeting either the kinase domain or the RNase domain. Herein, the recent advances in IRE1α pharmacological targeting is summarized. We describe the identification and optimization of IRE1α inhibitors as well as their mode of action and limitations as anticancer drugs. The potential pitfalls and challenges that could be faced in the clinic, and the opportunities that IRE1α modulating strategies may present are discussed.

Published
2020
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5. A novel blood brain barrier-permeable IRE1 kinase inhibitor sensitizes glioblastoma to chemotherapy in mice

Author

Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Xavier Guillory, Leif A. Eriksson, and Eric Chevet

Abstract

Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. We first characterized these candidates in vitro and in cellular models. We showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). From these inhibitors, we retained a Blood-Brain Barrier (BBB) permeable molecule (Z4P) and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB. We thus satisfy an unmet need for targeted, non-toxic, IRE1 inhibitors as adjuvant therapeutic agents against GB.

Published
2022
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7. Structure-Based Drug Discovery of IRE1 Modulators

Author

Diana, Pelizzari Raymundo, Leif A, Eriksson, Eric, Chevet, Xavier, Guillory, CRLCC Eugène Marquis (CRLCC), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Gothenburg (GU), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This work was funded by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National du Cancer (INCa, PLBIO2017, 18, 19, 20), Fondation pour la Recherche Médicale (FRM, équipe labellisée 2018), Agence National de la Recherche (ANR, eRaNet ERAAT, IRE1inNASH) to EC. DPR was funded by INSERM (LA VANNETAISE) and Région Bretagne SAD1. LAE acknowledges the support of The Swedish Research Council (Vetenskapsrådet), grant no 2019-3684, and the Swedish National Infrastructure for Computing (SNIC) for access to supercomputing resources of the supercomputing center C3SE in Gothenburg. This work has also been supported by the Fondation ARC pour la recherche sur le cancer, grant PDF20191209830, to XG., ANR-17-RAR3-0003,ERAAT,Enhancing Endoplasmic Reticulum Proteostasis to Rescue Alpha1 Antitrypsin Deficiency(2017), and ANR-18-CE14-0022,IRE1inNASH,Cibler la voie IRE1 dans la stéatohépatite(2018)

Subjects
Structure-based drug discovery (SBDD), Drug Discovery, Endoribonucleases, Unfolded Protein Response, Unfolded protein response computer assisted drug design (CADD), [SDV.CAN]Life Sciences [q-bio]/Cancer, IRE1, Protein Serine-Threonine Kinases, Endoplasmic Reticulum Stress, Endoplasmic reticulum
Abstract

International audience; IRE1α (inositol-requiring enzyme 1 alpha, referred to IRE1 hereafter) is an Endoplasmic Reticulum (ER) resident transmembrane enzyme with cytosolic kinase/RNAse activities. Upon ER stress IRE1 is activated through trans-autophosphorylation and oligomerization, resulting in a conformational change of the RNase domain, thereby promoting two signaling pathways: i) the non-conventional splicing of XBP1 mRNA and ii) the regulated IRE1-dependent decay of RNA (RIDD). IRE1 RNase activity has been linked to diverse pathologies such as cancer or inflammatory, metabolic, and degenerative diseases and the modulation of IRE1 activity is emerging as an appealing therapeutic strategy against these diseases. Several modulators of IRE1 activity have been reported in the past, but none have successfully translated into the clinics as yet. Based on our expertise in the field, we describe in this chapter the approaches and protocols we used to discover novel IRE1 modulators and characterize their effect on IRE1 activity.

Published
2022
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8. Structural and molecular bases to IRE1 activity modulation

Author

Nicolas Gouault, Timothy Langlais, Xavier Guillory, Eric Chevet, François Carreaux, Diana Pelizzari-Raymundo, Leif A. Eriksson, Sayyed Jalil Mahdizadeh, Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Gothenburg (GU), Institut National du Cancer (INCa PLBIO) Institut National du Cancer (INCA) France, Fondation pour la Recherche Medicale (FRM) Fondation pour la Recherche Medicale [DEQ20180339169], ERANET, Agence Nationale de la Recherche (ERAAT) French National Research Agency (ANR), EU European Commission [H2020 MSCA ITN-675448, MSCA RISE-734749], Swedish Research Council (VR) Swedish Research Council [2019-3684], Vinnova Seal-of-Excellence programVinnova [2019-02205], Ecole Doctorale 3M, university of Rennes 1, Region BretagneRegion Bretagne, Fondation ARC pour la recherche sur le cancerFondation ARC pour la Recherche sur le Cancer [PDF20191209830], Vinnova Seal-of-Excellence program Vinnova [2019-02205], Region Bretagne Region Bretagne, Fondation ARC pour la recherche sur le cancer Fondation ARC pour la Recherche sur le Cancer [PDF20191209830], European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), European Project: 777657,H2020-EU.1.3.3. - Stimulating innovation by means of cross-fertilisation of knowledge,777657,MSCA-RISE(2018), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CRLCC Eugène Marquis (CRLCC)

Subjects
Protein Folding, RNase P, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, IRE1, Protein Serine-Threonine Kinases, Endoplasmic Reticulum, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endoribonucleases, Animals, Homeostasis, Humans, [CHIM]Chemical Sciences, Enzyme Inhibitors, Mode of action, Molecular Biology, 030304 developmental biology, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Kinase, Chemistry, Endoplasmic reticulum, structure activity relationship (SAR), Cell Biology, unfolded protein response, Endoplasmic Reticulum Stress, Transmembrane protein, Cell biology, Cytosol, structure-based drug design (SBDD), 030220 oncology & carcinogenesis, Unfolded protein response, Protein folding, ER stress, Signal Transduction
Abstract

International audience; The Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules.

Published
2021
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9. The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

Author

Gwénaële Jégou, Eric Lippert, Francois-Xavier Mahon, Béatrice Turcq, Olivier Mansier, Eric Chevet, Konstantinos Voutetakis, Diana Pelizzari Raymundo, Pierre-Yves Dumas, Kim Barroso, Chloé James, Vincent Praloran, Valérie Lagarde, Valérie Prouzet-Mauléon, Aristotelis Chatziioannou, Jean-François Viallard, Jean-Max Pasquet, Aurélie Chauveau, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Service d'Hématologie [Bordeaux], CHU Bordeaux [Bordeaux], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Centre National de la Recherche Scientifique (CNRS), Service de Médecine Interne [CHU de Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU de Bordeaux], Institute of Chemical Biology [Athens, Greece], National Hellenic Research Foundation [Athens], Department of Biochemistry and Biotechnology [Larissa, Greece], University of Thessaly [Volos] (UTH), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Cancer Research, XBP1, MPN, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endoplasmic-reticulum-associated protein degradation, Protein degradation, Article, calreticulin, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], biology, Chemistry, Endoplasmic reticulum, food and beverages, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, ERAD, 3. Good health, Cell biology, endoplasmic reticulum, 030104 developmental biology, Oncology, Article RECHERCHE, 030220 oncology & carcinogenesis, biology.protein, Unfolded protein response, STAT protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Janus kinase, Calreticulin
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 &ndash, 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.

Published
2019
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