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1. ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?

Author

Manon Jaud, Christian Touriol, Kevin Rouault-Pierre, Doriana Di Bella, Stéphane Pyronnet, Kelly Féral, Laurent Mazzolini, Céline Philippe, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Queen Mary University of London (QMUL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mazzolini, Laurent

Subjects
0301 basic medicine, unfolded protein response (UPR), leukemia, lcsh:QR1-502, Activating transcription factor, Apoptosis, Review, Endoplasmic Reticulum, Biochemistry, lcsh:Microbiology, eIF-2 Kinase, 0302 clinical medicine, AML, Tumor Microenvironment, Homeostasis, unfolded protein response (UPR), CML, Gene Expression Regulation, Leukemic, leukemia, Lipids, 3. Good health, Cell biology, Mitochondria, 030220 oncology & carcinogenesis, endoplasmic reticulum stress, Signal transduction, Signal Transduction, endocrine system, Cell Survival, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Protein Serine-Threonine Kinases, DNA, Mitochondrial, digestive system, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Endoribonucleases, Autophagy, Animals, Humans, Protein kinase A, Molecular Biology, Ions, ATF6, Endoplasmic reticulum, fungi, Activating Transcription Factor 6, 030104 developmental biology, Proteostasis, Cancer cell, biological sciences, Unfolded protein response, Unfolded Protein Response, Calcium, ALL, CLL
Abstract

International audience; The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)-allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases.

Published
2021
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2. A novel leukemic route of mutant NPM1 through nuclear import of the overexpressed long noncoding RNA LONA

Author

Morgane Gourvest, Etienne De Clara, Hsin-Chieh Wu, Christian Touriol, Fabienne Meggetto, Hugues De Thé, Stéphane Pyronnet, Pierre Brousset, Marina Bousquet, MEGGETTO, Fabienne, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d’Excellence ‘TOUCAN’ [Toulouse], Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Oncologie cellulaire et moléculaire, Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Oncologie cellulaire et moléculaire, and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, Male, Cancer Research, Cytoplasm, [SDV.BA] Life Sciences [q-bio]/Animal biology, Carcinogenesis, Mutant, Active Transport, Cell Nucleus, HL-60 Cells, Mice, SCID, Biology, medicine.disease_cause, Article, Acute myeloid leukaemia, 03 medical and health sciences, Mice, 0302 clinical medicine, Myeloid Cell Differentiation, Mice, Inbred NOD, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Tumor Microenvironment, Animals, Humans, RNA, Messenger, Nuclear export signal, Cell Nucleus, Mutation, Gene Expression Regulation, Leukemic, [SDV.BA]Life Sciences [q-bio]/Animal biology, Wild type, Myeloid leukemia, Nuclear Proteins, Cell Differentiation, Hematology, Oncogenes, 3. Good health, Cell biology, Leukemia, Myeloid, Acute, 030104 developmental biology, Oncology, MAFB, 030220 oncology & carcinogenesis, Differentiation, RNA, Long Noncoding, Nuclear transport, Nucleophosmin
Abstract

International audience; The most frequent genetic alteration in acute myeloid leukemia (AML) is the mutation of nucleophosmin 1 (NPM1). Yet, its downstream oncogenic routes are not fully understood. Here, we report the identification of one long noncoding RNA (lncRNA) overexpressed in NPM1-mutated AML patients (named LONA) whose intracellular localization inversely reflects that of NPM1. While NPM1 is nuclear and LONA cytoplasmic in wild-type NPM1 AML cells, LONA becomes nuclear as mutant NPM1 moves toward the cytoplasm. Gain or loss of function combined with a genome-wide RNA-seq search identified a set of LONA mRNA targets encoding proteins involved in myeloid cell differentiation (including THSB1, MAFB, and ASB2) and interaction with its microenvironment. Consistently, LONA overexpression in mutant NPM1 established cell lines and primary AML cells exerts an anti-myeloid differentiation effect, whilst it exerts an opposite promyeloid differentiation effect in a wild type NPM1 setting. In vivo, LONA overexpression acts as an oncogenic lncRNA reducing the survival of mice transplanted with AML cells and rendering AML tumors more resistant to AraC chemotherapy. These data indicate that mutation-dependent nuclear export of NPM1 leads to nuclear retention and consequent oncogenic functions of the overexpressed lncRNA LONA, thus uncovering a novel NPM1 mutation-dependent pathway in AML pathogenesis.

Published
2021
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3. Differential Regulation of the Three Eukaryotic mRNA Translation Initiation Factor (eIF) 4Gs by the Proteasome

Author

Patrice Vende, Robert J. Schneider, Frédéric Lopez, Yvan Martineau, Didier Poncet, Christine Jean, Corinne Bousquet, Bertrand Fabre, Stéphane Pyronnet, Amandine Alard, Catherine Marboeuf, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie Moléculaire des Rotavirus (ROTA), Département Virologie (Dpt Viro), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), La Ligue Contre le Cancer (programme Equipes Labellisees), Investissements d'Avenir via the program CAPTOR, Investissements d'Avenir via the program LABEX TOUCAN, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), SERRE, Marie-Claude, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pyronnet, Stéphane, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay

Subjects
0301 basic medicine, proteolysis, site-mediated translation, mRNA translation, lcsh:QH426-470, Proteolysis, 20s proteasome, [SDV]Life Sciences [q-bio], Pest, eIF4G, DAP5, PEST, NQO1, NRF2, proteasome, oxidative stress, Nrf2, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Eukaryotic translation, nad(p)h, expression, Protein biosynthesis, medicine, Genetics, Gene silencing, Initiation factor, Genetics (clinical), Original Research, degradation, medicine.diagnostic_test, Proteasome, Chemistry, EIF4G, phosphorylation, pathway, protein-synthesis, Cell biology, [SDV] Life Sciences [q-bio], lcsh:Genetics, Oxidative Stress, 030104 developmental biology, 030220 oncology & carcinogenesis, Molecular Medicine, ornithine-decarboxylase, Intracellular
Abstract

WOS:000462822100001; International audience; The 4G family of eukaryotic mRNA translation initiation factors is composed of three members (eIF4GI, eIF4GII, and DAP5). Their specific roles in translation initiation are under intense investigations, but how their respective intracellular amounts are controlled remains poorly understood. Here we show that eIF4GI and eIF4GII exhibit much shorter half-lives than that of DAP5. Both eIF4GI and eIF4GII proteins, but not DAP5, contain computer-predicted PEST motifs in their N-termini conserved across the animal kingdom. They are both sensitive to degradation by the proteasome. Under normal conditions, eIF4GI and eIF4GII are protected from proteasomal destruction through binding to the detoxifying enzyme NQO1 [NAD(P)H:quinone oxidoreductase]. However, when cells are exposed to oxidative stress both eIF4GI and eIF4GII, but not DAP5, are degraded by the proteasome in an N-terminal-dependent manner, and cell viability is more compromised upon silencing of DAP5. These findings indicate that the three eIF4G proteins are differentially regulated by the proteasome and that persistent DAP5 plays a role in cell survival upon oxidative stress.

Published
2019
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4. Reversing pancreatic cancer metastasis through pharmacological targeting of pancreatic stellate cell's dialog with M2 macrophages

Author

Christine Jean, Julia Rochotte, Stéphane Pyronnet, Herbert A. Schmid, Yvan Martineau, Muriel Mathonnet, Stéphanie Cassant-Sourdy, Rémi Samain, Aurélie Perraud, Corinne Bousquet, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie digestive, endocrinienne et générale [CHU Limoges], CHU Limoges, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Novartis Pharmaceuticals, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Grenoble Alpes (UGA)

Subjects
Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Gastroenterology, Pancreatic stellate cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, 3. Good health, Metastasis, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Pancreatic cancer, medicine, Cancer research, 030211 gastroenterology & hepatology, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018
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5. Reversing pancreatic cancer immunosuppression through pharmacological targeting of activated pancreatic stellate cells

Author

Rémi Samain, Aurélie Perraud, Christine Jean, Julia Rochotte, Yvan Martineau, Corinne Bousquet, Herbert A. Schmid, Muriel Mathonnet, Stéphanie Cassant-Sourdy, Stéphane Pyronnet, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes (UGA), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Novartis Pharmaceuticals, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de Chirurgie digestive, endocrinienne et générale [CHU Limoges], CHU Limoges, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges

Subjects
Oncology, medicine.medical_specialty, Hepatology, business.industry, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Gastroenterology, Immunosuppression, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Pancreatic cancer, Internal medicine, Hepatic stellate cell, medicine, 030211 gastroenterology & hepatology, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2017
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6. Loss of Somatostatin Receptor Subtype 2 Promotes Growth of KRAS-Induced Pancreatic Tumors in Mice by Activating PI3K Signaling and Overexpression of CXCL16

Author

Marie Bernadette Delisle, Stéphanie Cassant-Sourdy, Takeshi Shimaoka, Marlène Dufresne, Marjorie Fanjul, Florence Breibach, Stéphane Pyronnet, Mary Poupot, Mounira Chalabi-Dchar, Corinne Bousquet, Camille Duluc, Muriel Mathonnet, Hubert Lulka, Rémi Samain, Catherine Roche, Shin Yonehara, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes (UGA), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Biomécanique et génie biomédical (BIM), Centre National de la Recherche Scientifique (CNRS), Service de Chirurgie digestive, endocrinienne et générale [CHU Limoges], CHU Limoges, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Chalabi-Dchar, Mounira, Cassant-Sourdy, Stephanie, Duluc, Camille, Fanjul, Marjorie, Lulka, Hubert, Samain, Remi, Roche, Catherine, Breibach, Florence, Delisle, Marie-Bernadette, Poupot, Mary, Dufresne, Marlene, Shimaoka, Takeshi, Yonehara, Shin, Mathonnet, Muriel, Pyronnet, Stephane, Bousquet, Corinne, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Chemokine CXCL6, Time Factors, endocrine system diseases, Pancreatic Intraepithelial Neoplasia, medicine.disease_cause, oncogene, Pancreatic tumor, Receptors, Somatostatin, Mice, Knockout, Receptors, Scavenger, NF-kappa B, Gastroenterology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Tumor Burden, Up-Regulation, 3. Good health, Phenotype, Lymphatic Metastasis, KRAS, Chemokines, CXC, signal transduction, Tumor Suppressor, Carcinoma, Pancreatic Ductal, Signal Transduction, Mice, 129 Strain, tumor suppressor, mouse model, Biology, Transfection, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Pancreatic cancer, medicine, Animals, Humans, Genetic Predisposition to Disease, Protein kinase B, PI3K/AKT/mTOR pathway, Oncogene, Cell Proliferation, Mouse Model, Gastroenterology & Hepatology, Hepatology, Chemokine CXCL16, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Pancreatic Neoplasms, Disease Models, Animal, Case-Control Studies, Mutation, Cancer research, Phosphatidylinositol 3-Kinase, Carcinogenesis, Proto-Oncogene Proteins c-akt
Abstract

Comment inSomatostatin receptor subtype 2 as pancreatic tumorigenesis suppressor: identification of a new targetable signaling node. [Gastroenterology. 2015]; International audience; BACKGROUND & AIMS:The KRAS gene is mutated in most pancreatic ductal adenocarcinomas (PDAC). Expression of this KRAS oncoprotein in mice is sufficient to initiate carcinogenesis but not progression to cancer. Activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is required for KRAS for induction and maintenance of PDAC in mice. The somatostatin receptor subtype 2 (sst2) inhibits PI3K, but sst2 expression is lost during the development of human PDAC. We investigated the effects of sst2 loss during KRAS-induced PDAC development in mice.METHODS:We analyzed tumor growth in mice that expressed the oncogenic form of KRAS (KRAS(G12D)) in pancreatic precursor cells, as well as sst2+/- and sst2-/-, and in crossed KRAS(G12D);sst2+/- and KRAS(G12D);sst2-/- mice. Pancreatic tissues and acini were collected and assessed by histologic, immunoblot, immunohistochemical, and reverse-transcription polymerase chain reaction analyses. We also compared protein levels in paraffin-embedded PDAC samples from patients vs heathy pancreatic tissues from individuals without pancreatic cancer.RESULTS:In sst2+/- mice, PI3K was activated and signaled via AKT (PKB; protein kinase B); when these mice were crossed with KRAS(G12D) mice, premalignant lesions, tumors, and lymph node metastases developed more rapidly than in KRAS(G12D) mice. In crossed KRAS(G12D);sst2+/- mice, activation of PI3K signaling via AKT resulted in activation of nuclear factor-κB (NF-κB), which increased KRAS activity and its downstream pathways, promoting initiation and progression of neoplastic lesions. We found this activation loop to be mediated by PI3K-induced production of the chemokine CXCL16. Administration of a CXCL16-neutralizing antibody to KRAS(G12D) mice reduced activation of PI3K signaling to AKT and NF-κB, blocking carcinogenesis. Levels of CXCL16 and its receptor CXCR6 were significantly higher in PDAC tissues and surrounding acini than in healthy pancreatic tissues from mice or human beings. In addition, expression of sst2 was progressively lost, involving increased PI3K activity, in mouse lesions that expressed KRAS(G12D) and progressed to PDAC.CONCLUSIONS:Based on analyses of mice, loss of sst2 from pancreatic tissues activates PI3K signaling via AKT, leading to activation of NF-κB, amplification of oncogenic KRAS signaling, increased expression of CXCL16, and pancreatic tumor formation. CXCL16 might be a therapeutic target for PDAC.

Published
2015
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7. Rotavirus NSP3 Is a Translational Surrogate of the Poly(A) Binding Protein-Poly(A) Complex

Author

Matthieu Gratia, Carolina Hilma Baron, Mariela Duarte, Stéphane Pyronnet, Annie Charpilienne, Didier Poncet, Patrice Vende, Emeline Sarot, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Moléculaire des Rotavirus (ROTA), Département Virologie (Dpt Viro), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Agence Nationale de la Recherche ANR-09-MIEN-04 Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche ANR

Subjects
Rotavirus, Polyadenylation, Viral protein, viruses, [SDV]Life Sciences [q-bio], Immunology, Messenger, Viral Nonstructural Proteins, medicine.disease_cause, Transfection, Microbiology, Poly(A)-Binding Proteins, Rotavirus Infections, Cell Line, chemistry.chemical_compound, Virology, Cricetinae, Poly(A)-binding protein, Protein biosynthesis, medicine, Animals, Humans, RNA, Messenger, Viral, Messenger RNA, biology, EIF4G, Rotavirus translation, Translation (biology), Molecular biology, Macaca mulatta, Genome Replication and Regulation of Viral Gene Expression, Eukaryotic Initiation Factor-4E, Electroporation, chemistry, Insect Science, Protein Biosynthesis, biology.protein, RNA, Viral, RNA, Eukaryotic Initiation Factor-4G, Poly A, HeLa Cells, Protein Binding
Abstract

Through its interaction with the 5′ translation initiation factor eIF4G, poly(A) binding protein (PABP) facilitates the translation of 5′-capped and 3′-poly(A)-tailed mRNAs. Rotavirus mRNAs are capped but not polyadenylated, instead terminating in a 3′ GACC motif that is recognized by the viral protein NSP3, which competes with PABP for eIF4G binding. Upon rotavirus infection, viral, GACC-tailed mRNAs are efficiently translated, while host poly(A)-tailed mRNA translation is, in contrast, severely impaired. To explore the roles of NSP3 in these two opposing events, the translational capabilities of three capped mRNAs, distinguished by either a GACC, a poly(A), or a non-GACC and nonpoly(A) 3′ end, have been monitored after electroporation of cells expressing all rotavirus proteins (infected cells) or only NSP3 (stably or transiently transfected cells). In infected cells, we found that the magnitudes of translation induction (GACC-tailed mRNA) and translation reduction [poly(A)-tailed mRNA] both depended on the rotavirus strain used but that translation reduction not genetically linked to NSP3. In transfected cells, even a small amount of NSP3 was sufficient to dramatically enhance GACC-tailed mRNA translation and, surprisingly, to slightly favor the translation of both poly(A)- and nonpoly(A)-tailed mRNAs, likely by stabilizing the eIF4E-eIF4G interaction. These data suggest that NSP3 is a translational surrogate of the PABP-poly(A) complex; therefore, it cannot by itself be responsible for inhibiting the translation of host poly(A)-tailed mRNAs upon rotavirus infection. IMPORTANCE To control host cell physiology and to circumvent innate immunity, many viruses have evolved powerful mechanisms aimed at inhibiting host mRNA translation while stimulating translation of their own mRNAs. How rotavirus tackles this challenge is still a matter of debate. Using rotavirus-infected cells, we show that the magnitude of cellular poly(A) mRNA translation differs with respect to rotavirus strains but is not genetically linked to NSP3. Using cells expressing rotavirus NSP3, we show that NSP3 alone not only dramatically enhances rotavirus-like mRNA translation but also enhances poly(A) mRNA translation rather than inhibiting it, likely by stabilizing the eIF4E-eIF4G complex. Thus, the inhibition of cellular polyadenylated mRNA translation during rotavirus infection cannot be attributed solely to NSP3 and is more likely the result of global competition between viral and host mRNAs for the cellular translation machinery.

Published
2015
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8. Netrin-1 mediates early events in pancreatic adenocarcinoma progression, acting on tumor and endothelial cells

Author

John Herbert, Vincent Castronovo, Andreas Bikfalvi, Martin Hagedorn, Corinne Bousquet, Roy Bicknell, Martin K. Schilling, Cathy Quemener, Laurent Dumartin, Hanane Laklai, Stéphane Pyronnet, Simon, Marie Francoise, Mécanismes moléculaires de l'angiogénèse, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Divisions of Immunity and Infection and Cancer Studies, University of Birmingham [Birmingham], Metastasis Research Laboratory, Center of Experimental Cancer Research, Université de Liège, Department of General, Visceral, Vascular and Pediatric Surgery, and Saarland University [Saarbrücken]

Subjects
Stromal cell, MESH: Cell Line, Tumor, CA-19-9 Antigen, endocrine system diseases, Angiogenesis, Apoptosis, Chick Embryo, Adenocarcinoma, Biology, MESH: CA-19-9 Antigen, MESH: Gene Expression Profiling, Cell Line, Tumor, Thrombospondin 1, medicine, Animals, Humans, Gene silencing, Neoplasm Invasiveness, MESH: Animals, MESH: Tumor Suppressor Proteins, MESH: Endothelial Cells, Nerve Growth Factors, CD151, MESH: Humans, Hepatology, MESH: Nerve Growth Factors, Gene Expression Profiling, Tumor Suppressor Proteins, MESH: Apoptosis, MESH: Adenocarcinoma, Gastroenterology, Endothelial Cells, MESH: Neoplasm Invasiveness, Netrin-1, MESH: Chick Embryo, medicine.disease, Molecular biology, digestive system diseases, Pancreatic Neoplasms, Endothelial stem cell, Disease Progression, Cancer research, Human umbilical vein endothelial cell, MESH: Disease Progression, MESH: Pancreatic Neoplasms
Abstract

International audience; BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. It is characterized by substantial tumor cell invasion and early-stage metastasis. We developed an in vivo model to analyze interactions between cancer and stromal cells during early stages of PDAC. METHODS: Human pancreatic adenocarcinoma cells were grafted onto the chick chorioallantoic membrane (CAM). Human and chicken GeneChips were used simultaneously to study gene regulation during PDAC cell invasion. Bioinformatic analysis was used to identify human orthologs and cell specificity of gene expression. The effects of netrin-1 encoded by NTN1 were investigated in adhesion, invasion, and apoptosis assays. The effects of NTN1 silencing with small interfering RNAs were investigated in PDAC cells in vivo. NTN1 expression was measured in human PDAC samples. RESULTS: PDAC cells rapidly invade the CAM stroma and remodel the CAM vasculature. Around 800 stromal genes were up-regulated by >2-fold; the angiogenesis regulators vascular endothelial growth factor D, thrombospondin 1, and CD151 were among the most highly regulated genes. Silencing of tumor cell NTN1, which is up-regulated 4-fold in the PDAC model, inhibited tumor cell invasion in vivo. Netrin-1 conferred apoptosis resistance to tumor and endothelial cells in vitro, induced their invasion, and provided an adhesive substrate for tumor cells. NTN1 and its gene product are strongly overexpressed in human PDAC samples. CONCLUSIONS: We developed a useful tool to study the invasive mechanisms of early-stage PDAC. Netrin-1 might be an important regulator of pancreatic tumor growth that functions in tumor and endothelial cells.

Published
2010
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9. NAD(P)H quinone-oxydoreductase 1 protects eukaryotic translation initiation factor 4GI from degradation by the proteasome

Author

Rodica Anesia, Stéphane Pyronnet, Philippe Pierre, Corinne Bousquet, Bertrand Fabre, Christiane Susini, Amandine Alard, Catherine Marboeuf, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chirurgie Générale et Digestive [Rangueil], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], and Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Small interfering RNA, MESH: NAD(P)H Dehydrogenase (Quinone), Mice, Peptide Initiation Factors, Chlorocebus aethiops, NAD(P)H Dehydrogenase (Quinone), Protein biosynthesis, MESH: Animals, MESH: Peptide Initiation Factors, MESH: Peptide Fragments, 0303 health sciences, MESH: Protease Inhibitors, MESH: Oxidative Stress, Protein Stability, MESH: Proteasome Endopeptidase Complex, 030302 biochemistry & molecular biology, Articles, Transfection, MESH: Eukaryotic Initiation Factor-4G, Biochemistry, MESH: Protein Biosynthesis, Proteasome Inhibitors, Protein Binding, Proteasome Endopeptidase Complex, MESH: NADPH Dehydrogenase, Biology, Cell Line, 03 medical and health sciences, Eukaryotic translation, MESH: Protein Stability, Animals, Humans, Initiation factor, MESH: Protein Binding, Protease Inhibitors, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, NADPH Dehydrogenase, Cell Biology, MESH: Cercopithecus aethiops, Peptide Fragments, MESH: Cell Line, Oxidative Stress, Proteasome, Protein Biosynthesis, NAD+ kinase, Eukaryotic Initiation Factor-4G
Abstract

International audience; The eukaryotic translation initiation factor 4GI (eIF4GI) serves as a central adapter in cap-binding complex assembly. Although eIF4GI has been shown to be sensitive to proteasomal degradation, how the eIF4GI steady-state level is controlled remains unknown. Here, we show that eIF4GI exists in a complex with NAD(P)H quinone-oxydoreductase 1 (NQO1) in cell extracts. Treatment of cells with dicumarol (dicoumarol), a pharmacological inhibitor of NQO1 known to preclude NQO1 binding to its protein partners, provokes eIF4GI degradation by the proteasome. Consistently, the eIF4GI steady-state level also diminishes upon the silencing of NQO1 (by transfection with small interfering RNA), while eIF4GI accumulates upon the overexpression of NQO1 (by transfection with cDNA). We further reveal that treatment of cells with dicumarol frees eIF4GI from mRNA translation initiation complexes due to strong activation of its natural competitor, the translational repressor 4E-BP1. As a consequence of cap-binding complex dissociation and eIF4GI degradation, protein synthesis is dramatically inhibited. Finally, we show that the regulation of eIF4GI stability by the proteasome may be prominent under oxidative stress. Our findings assign NQO1 an original role in the regulation of mRNA translation via the control of eIF4GI stability by the proteasome.

Published
2010
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10. Control of contact-inhibition by 4E-BP1 upregulation

Author

Rania Azar, Corinne Bousquet, Stéphane Pyronnet, Christiane Susini, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cell type, Cell cycle checkpoint, Cyclin A, Blotting, Western, Cell Cycle Proteins, environment and public health, Cyclin D1, Cell Line, Tumor, Humans, Immunoprecipitation, Promoter Regions, Genetic, Molecular Biology, Adaptor Proteins, Signal Transducing, Cell Proliferation, biology, Cell growth, Cell Cycle, fungi, G1 Phase, Contact inhibition, Cell Biology, Transfection, Cell cycle, Flow Cytometry, Phosphoproteins, Cell biology, enzymes and coenzymes (carbohydrates), biology.protein, biological phenomena, cell phenomena, and immunity, Developmental Biology
Abstract

International audience; Although contact inhibition is a fundamental process for multicellular organisms, how proliferation is inhibited at high cellular densities remains poorly characterized. Here we show that 4E-BP1, one major repressor of cap-dependent translation, plays a critical role in density-mediated cell cycle arrest. 4E-BP1 promoter is activated and 4E-BP1 protein amount increases as cells reach confluence. Conversely, a much less marked density-dependent inhibition of cell proliferation is observed upon 4E-BP1 silencing. We further show that at high density, progression through the G(1) phase of the cell cycle is faster and Cyclin D1 protein is induced in different cell types where 4E-BP1 has been either downregulated (stable shRNA expression or transient siRNA transfection) or removed (knockout). Thus 4E-BP1 appears as an important mediator of contact inhibition.

Published
2010

11. Antitumor effects of somatostatin

Author

Stéphane Pyronnet, Christiane Susini, Souad Najib, Hanane Laklai, Rania Azar, Corinne Bousquet, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise

Subjects
MESH: Signal Transduction, Pituitary gland, MESH: Somatostatin, Apoptosis, MESH: Cell Cycle, Biochemistry, 0302 clinical medicine, Endocrinology, Neoplasms, Somatostatin receptor 3, MESH: Human Growth Hormone, Somatostatin receptor 2, Somatostatin receptor 1, MESH: Animals, MESH: Neoplasms, Receptors, Somatostatin, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Somatostatin receptor, Human Growth Hormone, Cell Cycle, Life Sciences, MESH: Antineoplastic Agents, Hormonal, 3. Good health, medicine.anatomical_structure, Somatostatin, 030220 oncology & carcinogenesis, Pancreas, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, medicine.medical_specialty, endocrine system, Antineoplastic Agents, Hormonal, Biology, 03 medical and health sciences, Internal medicine, MESH: Cell Proliferation, medicine, MESH: Receptors, Somatostatin, Endocrine system, Animals, Humans, Molecular Biology, 030304 developmental biology, Cell Proliferation, MESH: Humans, MESH: Apoptosis, Cancer research
Abstract

International audience; Since its discovery three decades ago as an inhibitor of GH release from the pituitary gland, somatostatin has attracted much attention because of its functional role in the regulation of a wide variety of physiological functions in the brain, pituitary, pancreas, gastrointestinal tract, adrenals, thyroid, kidney and immune system. In addition to its negative role in the control of endocrine and exocrine secretions, somatostatin and analogs also exert inhibitory effects on the proliferation and survival of normal and tumor cells. Over the past 15 years, studies have begun to reveal some of the molecular mechanisms underlying the antitumor activity of somatostatin. This review covers the present knowledge in the antitumor effect of somatostatin and analogs and discusses the perspectives of novel clinical strategies based on somatostatin receptor sst2 gene transfer therapy.

Published
2008
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12. High tumorigenic potential of a constitutively active mutant of the cholecystokinin 2 receptor

Author

Daniel Fourmy, Marc Poirot, Daniel Cussac, Louis Buscail, Céline Galés, Didier Sanchez, Sandrine Silvente-Poirot, Lucien Pradayrol, Stéphane Pyronnet, Biologie et Pathologie Digestive, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud, Pharmacologie Moleculaire et Physiopathologie Renale, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Poirot, Marc

Subjects
Cancer Research, MESH: 3T3 Cells, Mutant, Amino Acid Motifs, Cell morphology, Ornithine decarboxylase, Mice, MESH: Amino Acid Motifs, 0302 clinical medicine, MESH: Animals, Receptor, Cholecystokinin, 0303 health sciences, Alanine, 3T3 Cells, MESH: Glutamic Acid, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Cell biology, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Ornithine Decarboxylase, Cell Transformation, Neoplastic, Biochemistry, 030220 oncology & carcinogenesis, MESH: Phospholipase C, MESH: Cell Division, Female, Signal transduction, Cell Division, MESH: Enzyme Activation, Carcinogenicity Tests, MESH: Alanine, Glutamic Acid, Mice, Nude, Biology, Ornithine Decarboxylase, 03 medical and health sciences, Genetics, MESH: Mice, Nude, Animals, Humans, Point Mutation, MESH: Receptor, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Point Mutation, MESH: Humans, Phospholipase C, Cell growth, Receptor, Cholecystokinin B, Enzyme Activation, MESH: Cell Transformation, Neoplastic, Type C Phospholipases, MESH: Carcinogenicity Tests, Receptors, Cholecystokinin, MESH: Female
Abstract

The cholecystokinin 2 receptor (CCK2R) increases proliferation of normal and neoplastic gastrointestinal cells and activates various mitogenic signaling pathways when stimulated by gastrin. To study the incidence of permanent activation of this receptor in tumorigenicity, a constitutively active mutant was generated by replacing residue Glu151 in the conserved E/DRY motif by Ala. Expression of the E151A-CCK2R mutant in NIH-3T3 cells causes ligand-independent activation of phospholipase C and ornithine decarboxylase, two enzymes critical for mitogenesis. Strikingly, the constitutive activity of this mutant was associated with dramatic alteration of NIH-3T3 cell morphology, enhanced cell proliferation and invasion. Moreover, injection of cells expressing E151A-CCK2R in nude mice resulted in the development of large and rapidly growing tumors. By contrast, none of these effects was observed with cells expressing the wild-type CCK2R, indicating that the tumorigenic properties of the E151A-CCK2R mutant is the result of its constitutive activation. To date, this is the first report that provides evidence for the high tumorigenic effect of a constitutively active CCK2R mutant, thus raising a potential role of the CCK2R in human cancer.

Published
2003
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