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7 results on '"Université de Reims Champagne-Ardenne (URCA)-JE2428"'

1. Accumulation of lactosylceramide and overexpression of a PSC833-resistant P-glycoprotein in multidrug-resistant human sarcoma cells

Author

Nassera Aouali, Lahcen Eddabra, Hassan El Btaouri, Claudie Madoulet, Hamid Morjani, Charles Dumontet, Sophie Malagarie-Cazenave, Equipe 14, Oncogénèse et progression tumorale, 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 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 de Recherche en Cancérologie de Lyon ( CRCL ), 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 National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Onco-Pharmacologie ( LOP ), Université de Reims Champagne-Ardenne ( URCA ) -JE2428, Université de Reims Champagne-Ardenne ( URCA ), 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 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 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)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Onco-Pharmacologie (LOP), Université de Reims Champagne-Ardenne (URCA)-JE2428, and Université de Reims Champagne-Ardenne (URCA)

Subjects
Cancer Research, MESH : RNA, Messenger, MESH: Flow Cytometry, MESH : Blotting, Western, MESH : Lactosylceramides, MESH : P-Glycoprotein, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, MESH : Tumor Cells, Cultured, MESH: Reverse Transcriptase Polymerase Chain Reaction, Cyclosporin a, Tumor Cells, Cultured, polycyclic compounds, MESH : Cell Proliferation, Cytotoxic T cell, MESH: Cyclosporins, MESH: Antigens, CD, P-glycoprotein, 0303 health sciences, music.instrument, Antibiotics, Antineoplastic, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, Sarcoma, General Medicine, Flow Cytometry, MESH: Drug Resistance, Neoplasm, Drug Resistance, Multiple, MESH : Antibiotics, Antineoplastic, 3. Good health, MESH : Drug Resistance, Neoplasm, Oncology, Biochemistry, 030220 oncology & carcinogenesis, MESH: Daunorubicin, medicine.drug, MESH: P-Glycoprotein, Daunorubicin, MESH : Flow Cytometry, Blotting, Western, Lactosylceramides, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cyclosporins, MESH : Sarcoma, MESH: Drug Resistance, Multiple, MESH: Doxorubicin, 03 medical and health sciences, Lactosylceramide, Antigens, CD, MESH: Cell Proliferation, medicine, MESH : Antigens, CD, MESH: Blotting, Western, Humans, MESH : Doxorubicin, Doxorubicin, MESH: Tumor Cells, Cultured, ATP Binding Cassette Transporter, Subfamily B, Member 1, RNA, Messenger, MESH : Cyclosporins, MESH: Antibiotics, Antineoplastic, MESH: Lactosylceramides, music, MESH: RNA, Messenger, 030304 developmental biology, Cell Proliferation, MESH: Humans, MESH : Humans, Molecular biology, Multiple drug resistance, Cell culture, Drug Resistance, Neoplasm, MESH: Sarcoma, biology.protein, MESH : Daunorubicin, MESH : Drug Resistance, Multiple
Abstract

International audience; The selection pressure for resistance to chemotherapy is accompanied by the enhanced expression of ABC proteins and increased cellular glycosphingolipid content. Thus, a possible connection between glycosphingolipid metabolism and ABC proteins in drug resistance has been suggested. In the present study, we established two human multidrug-resistant (MDR) cell lines derived from MESSA sarcoma cells by culturing with increasing concentrations of doxorubicin (DX5 cells) or doxorubicin together with cyclosporin A (GARF cells). Both resistant cell lines overexpressed the MDR1 gene and the wild-type P-glycoprotein at the same level. The cyclosporin derivative PSC833, a potent inhibitor of P-glycoprotein, sensitized DX5 but not GARF cells to the cytotoxic effects of daunorubicin. Moreover, PSC833 increased the nuclear accumulation of daunorubicin and the cellular accumulation of [3H]vinblastine in the DX5 but not in the GARF cells. The cellular incorporation of [3H]-cyclosporin A was lower in DX5 cells compared to MESSA and GARF cells, which incorporated the same level of [3H]-cyclosporin A. Sphingolipid analysis showed that the lactosylceramide level was 2.5- and 5-fold higher in DX5 and GARF cells, respectively, than in MESSA cells. Whereas the pharmacological inhibition of lactosylceramide synthesis was able to reverse only partially the resistance of GARF cells to daunorubicin without significant increase in nuclear accumulation of the drug, the same treatment before the co-treatment with PSC833 and daunorubicin increased the cytotoxic effect of daunorubicin and its nuclear accumulation. These data suggest a possible relationship between lactosylceramide levels and the resistance of P-glycoprotein to modulation by MDR modulators.

Published
2011

2. Role of LRP-1 in cancer cell migration in 3-dimensional collagen matrix

Author

Aline Appert-Collin, Hamid Morjani, Pierre Jeannesson, Christine Terryn, Guy Fuhrmann, Stéphane Dedieu, Amar Bennasroune, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), EA2063 - biochimie et biologie moléculaire, Université de Reims Champagne-Ardenne (URCA), Interfaces biomatériaux/tissus hôtes, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Onco-Pharmacologie (LOP), Université de Reims Champagne-Ardenne (URCA)-JE2428, Laboratoire de Signalisation et Récepteurs Matriciels (SiRMa), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé)

Subjects
0301 basic medicine, Myosin Light Chains, MMP2, RHOA, Cell, LDL-receptor-related protein-associated protein, Extracellular matrix, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cell Movement, Cell Line, Tumor, medicine, Animals, Humans, Gene silencing, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, Thyroid Neoplasms, LDL-Receptor Related Protein-Associated Protein, Cell Shape, ComputingMilieux_MISCELLANEOUS, biology, Reproducibility of Results, Cell migration, Cell Biology, Recombinant Proteins, Extracellular Matrix, Rats, Cell biology, Enzyme Activation, 030104 developmental biology, medicine.anatomical_structure, Focal Adhesion Protein-Tyrosine Kinases, LDL receptor, biology.protein, lipids (amino acids, peptides, and proteins), Collagen, Low Density Lipoprotein Receptor-Related Protein-1, Research Paper
Abstract

The low-density lipoprotein receptor-related protein-1 (LRP-1) is a member of Low Density Lipoprotein Receptor (LDLR) family, which is ubiquitously expressed and which is described as a multifunctional endocytic receptor which mediates the clearance of various extracellular matrix molecules including serine proteinases, proteinase-inhibitor complexes, and matricellular proteins. Several studies showed that high LRP-1 expression promotes breast cancer cell invasiveness, and LRP-1 invalidation leads to cell motility abrogation in both tumor and non-tumor cells. Furthermore, our group has reported that LRP-1 silencing prevents the invasion of a follicular thyroid carcinoma despite increased pericellular proteolytic activities from MMP2 and uPA using a 2D-cell culture model. As the use of 3D culture systems is becoming more and more popular due to their promise as enhanced models of tissue physiology, the aim of the present work is to characterize for the first time how the 3D collagen type I matrix may impact the ability of LRP-1 to regulate the migratory properties of thyroid carcinoma using as a model FTC-133 cells. Our results show that inhibition of LRP-1 activity or expression leads to morphological changes affecting cell-matrix interactions, reorganizations of the actin-cytoskeleton especially by inhibiting FAK activation and increasing RhoA activity and MLC-2 phosphorylation, thus preventing cell migration. Taken together, our results suggest that LRP-1 silencing leads to a decrease of cell migratory capacity in a 3D configuration.

Published
2016

3. The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks

Author

Florence Larminat, Philippe Frit, Dennis Gomez, Oriane Bombarde, Carine Racca, Nicolas Guilbaud, Bruno Gomes, Patrick Calsou, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), 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)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Onco-Pharmacologie (LOP), Université de Reims Champagne-Ardenne (URCA)-JE2428, iTeos Therapeutics (iTeos), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), 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 JE2428-Université de Reims Champagne-Ardenne (URCA)

Subjects
0301 basic medicine, Cancer Research, [SDV]Life Sciences [q-bio], Genetic Vectors, RAD51, Apoptosis, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neoplasms, medicine, Polyamines, Humans, Topoisomerase II Inhibitors, DNA Breaks, Double-Stranded, Etoposide, ComputingMilieux_MISCELLANEOUS, Podophyllotoxin, Polyamine transport, BRCA1 Protein, Topoisomerase, Molecular biology, Chromatin, Cell biology, 030104 developmental biology, Cell killing, DNA Topoisomerases, Type II, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Rad51 Recombinase, DNA, medicine.drug
Abstract

Poisons of topoisomerase II (TOP2) kill cancer cells by preventing religation of intermediate DNA breaks during the enzymatic process and thus by accumulating enzyme–drug–DNA complexes called TOP2 cleavage-complex (TOP2cc). F14512 is a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived from etoposide and currently in clinical trials. It was shown in vitro that F14512 has acquired DNA-binding properties and that the stability of TOP2cc was strongly increased. Paradoxically, at equitoxic concentrations in cells, F14512 induced less DNA breaks than etoposide. Here, we directly compared etoposide and F14512 for their rates of TOP2cc production and resolution in human cells. We report that targeting of TOP2α and not TOP2β impacts cell killing by F14512, contrary to etoposide that kills cells through targeting both isoforms. Then, we show that despite being more cytotoxic, F14512 is less efficient than etoposide at producing TOP2α cleavage-complex (TOP2αcc) in cells. Finally, we report that compared with TOP2αcc mediated by etoposide, those generated by F14512 persist longer in the genome, are not dependent on TDP2 for cleaning break ends from TOP2α, are channeled to a larger extent to resection-based repair processes relying on CtIP and BRCA1 and promote RAD51 recruitment to damaged chromatin. In addition to the addressing of F14512 to the polyamine transport system, the properties uncovered here would be particularly valuable for a therapeutic usage of this new anticancer compound. More generally, the concept of increasing drug cytotoxicity by switching the repair mode of the induced DNA lesions via addition of a DNA-binding moiety deserves further developments. Mol Cancer Ther; 16(10); 2166–77. ©2017 AACR.

Published
2016

4. Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence

Author

Céline Douarre, Jean-François Riou, Hamid Morjani, Marie-Françoise O'Donohue, Chantal Trentesaux, Patrick Mailliet, Lahcen Eddabra, Dennis Gomez, Jean-Marie Zahm, Laboratoire d'Onco-Pharmacologie (LOP), Université de Reims Champagne-Ardenne (URCA)-JE2428, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Biospectroscopie Translationnelle - EA 7506 (BIOSPECT), Université de Reims Champagne-Ardenne (URCA), Plasticité de l'épithélium respiratoire dans les conditions normales et pathologiques - UMR-S 903 (PERPMP), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Département de chimie (SA), Sanofi-Aventis, Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), EA2063 - biochimie et biologie moléculaire, Acides nucléiques : dynamique, ciblage, et fonctions biologiques - Régulation et dynamique des génomes (ANDCFB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique cellulaire et moléculaire de la muqueuse respiratoire, Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM), Médicaments : Dynamique Intracellulaire et Architecture Nucléaire (MéDIAN), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), and Birembaut, Philippe

Subjects
Telomerase, MESH: Cell Line, Tumor, Guanine, MESH: Mitochondria, MESH: Triazines, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Quinolinium Compounds, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Genetics, medicine, Humans, Telomerase reverse transcriptase, Cellular Senescence, 030304 developmental biology, MESH: Guanine, A549 cell, 0303 health sciences, MESH: Humans, Triazines, MESH: Apoptosis, Quinolinium Compounds, Transfection, Telomere, MESH: Drug Resistance, Neoplasm, Cell biology, Mitochondria, MESH: Cell Aging, MESH: Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-bcl-2, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Antineoplastic Agents, MESH: Telomere, Cell aging, Camptothecin, medicine.drug
Abstract

International audience; The triazine derivative 12459 is a potent G-quadruplex interacting agent that inhibits telomerase activity. This agent induces time- and dose-dependent telomere shortening, senescence-like growth arrest and apoptosis in the human A549 tumour cell line. We show here that 12459 induces a delayed apoptosis that activates the mitochondrial pathway. A549 cell lines selected for resistance to 12459 and previously characterized for an altered hTERT expression also showed Bcl-2 overexpression. Transfection of Bcl-2 into A549 cells induced a resistance to the short-term apoptotic effect triggered by 12459, suggesting that Bcl-2 is an important determinant for the activity of 12459. In sharp contrast, the Bcl-2 overexpression was not sufficient to confer resistance to the senescence-like growth arrest induced by prolonged treatment with 12459. We also show that 12459 provokes a rapid degradation of the telomeric G-overhang in conditions that paralleled the apoptosis induction. In contrast, the G-overhang degradation was not observed when apoptosis was induced by camptothecin. Bcl-2 overexpression did not modify the G-overhang degradation, suggesting that this event is an early process uncoupled from the final apoptotic pathway.

Published
2005

5. Ataxia telangiectasia mutated activation by transcription‐ and topoisomerase I‐induced DNA double‐strand breaks

Author

Estelle Nicolas, Stéphanie Solier, Benu Brata Das, Chiara Conti, Céline Douarre, Olivier Sordet, William M. Bonner, Asako J. Nakamura, Susan Smith, Kurt W. Kohn, Josée Guirouilh-Barbat, Yves Pommier, Christophe E. Redon, Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institut Gustave Roussy (IGR), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire d'Onco-Pharmacologie (LOP), Université de Reims Champagne-Ardenne (URCA)-JE2428, Laboratory of Molecular Pharmacology, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), 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)-Centre de Biologie Intégrative (CBI), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Transcription, Genetic, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Biochemistry, Histones, 0302 clinical medicine, Transcription (biology), DNA Breaks, Double-Stranded, Lymphocytes, Enzyme Inhibitors, Checkpoint Kinase 2, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Alpha-Amanitin, Neurons, 0303 health sciences, Phosphorylated Histone H2AX, Microscopy, Confocal, biology, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Flow Cytometry, 3. Good health, DNA-Binding Proteins, DNA Topoisomerases, Type I, 030220 oncology & carcinogenesis, biological phenomena, cell phenomena, and immunity, Tumor Suppressor p53-Binding Protein 1, Signal Transduction, DNA damage, Scientific Report, Ribonuclease H, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protein Serine-Threonine Kinases, 03 medical and health sciences, Genetics, Animals, Humans, Molecular Biology, Adaptor Proteins, Signal Transducing, Nucleic Acid Synthesis Inhibitors, 030304 developmental biology, Tumor Suppressor Proteins, Topoisomerase, G2-M DNA damage checkpoint, Molecular biology, Rats, MDC1, enzymes and coenzymes (carbohydrates), Microscopy, Fluorescence, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Trans-Activators, biology.protein, Camptothecin, Dichlororibofuranosylbenzimidazole
Abstract

Ataxia telangiectasia mutated (ATM), the deficiency of which causes a severe neurodegenerative disease, is a crucial mediator for the DNA damage response (DDR). As neurons have high rates of transcription that require topoisomerase I (TOP1), we investigated whether TOP1 cleavage complexes (TOP1cc)-which are potent transcription-blocking lesions-also produce transcription-dependent DNA double-strand breaks (DSBs) with ATM activation. We show the induction of DSBs and DDR activation in post-mitotic primary neurons and lymphocytes treated with camptothecin, with the induction of nuclear DDR foci containing activated ATM, gamma-H2AX (phosphorylated histone H2AX), activated CHK2 (checkpoint kinase 2), MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1). The DSB-ATM-DDR pathway was suppressed by inhibiting transcription and gamma-H2AX signals were reduced by RNase H1 transfection, which removes transcription-mediated R-loops. Thus, we propose that Top1cc produce transcription arrests with R-loop formation and generate DSBs that activate ATM in post-mitotic cells.

Published
2009

6. Telomestatin-induced telomere uncapping is modulated by POT1 through G-overhang extension in HT1080 human tumor cells

Author

Jean-François Riou, Chantal Trentesaux, Marie-Françoise O'Donohue, Bertrand Brassart, Dennis Gomez, Céline Douarre, Victoria El Khoury, Kazuo Shin-ya, Hamid Morjani, Thomas Wenner, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire d'Onco-Pharmacologie (LOP), Université de Reims Champagne-Ardenne (URCA)-JE2428, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Biospectroscopie Translationnelle - EA 7506 (BIOSPECT), Université de Reims Champagne-Ardenne (URCA), EA2063 - biochimie et biologie moléculaire, Structure et Instabilité des Génomes (STRING), and Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Senescence, Chromatin Immunoprecipitation, DNA damage, Telomere Capping, [SDV]Life Sciences [q-bio], Green Fluorescent Proteins, Telomere-Binding Proteins, Fluorescent Antibody Technique, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 010402 general chemistry, 01 natural sciences, Biochemistry, Telomestatin, Shelterin Complex, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, Humans, Molecular Biology, Oxazoles, Uncapping, 030304 developmental biology, DNA Primers, 0303 health sciences, Base Sequence, Cell Biology, Telomere, Molecular biology, 3. Good health, 0104 chemical sciences, Cell biology, chemistry, Cancer cell, Chromatin immunoprecipitation, DNA Damage
Abstract

International audience; Telomestatin is a potent G-quadruplex ligand that interacts with the 3' telomeric overhang, leading to its degradation, and induces a delayed senescence and apoptosis of cancer cells. POT1 and TRF2 were recently identified as specific telomere-binding proteins involved in telomere capping and t-loop maintenance and whose interaction with telomeres is modulated by telomestatin. We show here that the treatment of HT1080 human tumor cells by telomestatin induces a rapid decrease of the telomeric G-overhang and of the double-stranded telomeric repeats. Telomestatin treatment also provokes a strong decrease of POT1 and TRF2 from their telomere sites, suggesting that the ligand triggers the uncapping of the telomere ends. The effect of the ligand is associated with an increase of the gamma-H2AX foci, one part of them colocalizing at telomeres, thus indicating the occurrence of a DNA damage response at the telomere, but also the presence of additional DNA targets for telomestatin. Interestingly, the expression of GFP-POT1 in HT1080 cells increases both telomere and G-overhang length. As compared with HT1080 cells, HT1080GFP-POT1 cells presented a resistance to telomestatin treatment characterized by a protection to the telomestatin-induced growth inhibition and the G-overhang shortening. This protection is related to the initial G-overhang length rather than to its degradation rate and is overcome by increased telomestatin concentration. Altogether these results suggest that telomestatin induced a telomere dysfunction in which G-overhang length and POT1 level are important factors but also suggest the presence of additional DNA sites of action for the ligand.

Published
2006

7. The G-quadruplex ligand telomestatin inhibits POT1 binding to telomeric sequences in vitro and induces GFP-POT1 dissociation from telomeres in human cells

Author

Jean-François Riou, Marie-Françoise O'Donohue, Jérome Macadré, Céline Douarre, Alain Kolkes, Hervé Kaplan, Kazuo Shin-ya, Pascale Koebel, Marie-Josèphe Giraud-Panis, Thomas Wenner, Dennis Gomez, Laboratoire d'Onco-Pharmacologie (LOP), Centre National de la Recherche Scientifique (CNRS), Médicaments : Dynamique Intracellulaire et Architecture Nucléaire (MéDIAN), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS 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), Laboratoire Joliot Curie, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), Biomolécules : interactions moléculaires, cellulaires et cellules-matrice extracellulaire (BIMCCME), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie moléculaire eucaryote (LBME), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Reims Champagne-Ardenne (URCA)-JE2428, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et pathologie des génomes, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine de Reims, Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Laboratory of Biology and Pathology of Genomes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Telomere localization, Telomere Capping, Recombinant Fusion Proteins, [SDV]Life Sciences [q-bio], Green Fluorescent Proteins, Telomere-Binding Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 010402 general chemistry, G-quadruplex, Kidney, Transfection, 01 natural sciences, Telomestatin, Shelterin Complex, Green fluorescent protein, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Humans, Telomeric Repeat Binding Protein 2, Oxazoles, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Telomere-binding protein, 0303 health sciences, Nuclear Proteins, DNA, Telomere, Molecular biology, 0104 chemical sciences, G-Quadruplexes, Oncology, chemistry, Cancer cell, TATA Box Binding Protein-Like Proteins, Protein Binding
Abstract

Telomestatin is a potent G-quadruplex ligand that specifically interacts with the 3′ telomeric overhang, leading to its degradation and that induces a delayed senescence and apoptosis of cancer cells. Protection of Telomere 1 (POT1) was recently identified as a specific single-stranded telomere-binding protein involved in telomere capping and T-loop maintenance. We showed here that a telomestatin treatment inhibits POT1 binding to the telomeric overhang in vitro. The treatment of human EcR293 cells by telomestatin induces a dramatic and rapid delocalization of POT1 from its normal telomere sites but does not affect the telomere localization of the double-stranded telomere-binding protein TRF2. Thus, we propose that G-quadruplex stabilization at telomeric G-overhang inactivates POT1 telomeric function, generating a telomere dysfunction in which chromosome ends are no longer properly protected. (Cancer Res 2006; 66(14): 6908-12)

Published
2006

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