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1. Cooperation of amphiregulin and insulin-like growth factor-1 inhibits Bax- and Bad-mediated apoptosis via a protein kinase C-dependent pathway in non-small cell lung cancer cells.: Bad and Bax inactivation by AR/IGF1-PKC-dependent pathway

Author

Christian Brambilla, Patrick Auberger, Marie-Christine Favrot, Jean-Luc Coll, Amandine Hurbin, Laurence Dubrez-Daloz, Bernard Mari, Groupe de Recherche Sur Le Cancer du Poumon : Bases Moléculaires de la Progression Tumorale, Dépistage et Thérapie Génique, Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiopathologie de la survie et de la mort cellulaire et infection virale, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR50-Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)

Subjects
MAPK/ERK pathway, Lung Neoplasms, Apoptosis, MESH : Insulin-Like Growth Factor I, Biochemistry, Culture Media, Serum-Free, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Flavonoids, Wortmannin, 0302 clinical medicine, MESH : 1-Phosphatidylinositol 3-Kinase, Enzyme Inhibitors, MESH : Isoenzymes, 0303 health sciences, Kinase, MESH: Culture Media, Serum-Free, 3. Good health, Cell biology, Calphostin C, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, MESH : bcl-Associated Death Protein, MESH : Carrier Proteins, MAP Kinase Signaling System, MESH: Carrier Proteins, Naphthalenes, Article, 03 medical and health sciences, Bcl-2-associated X protein, MESH: bcl-Associated Death Protein, Humans, MESH : Lung Neoplasms, Molecular Biology, Glycoproteins, MESH: Humans, MESH : Carcinoma, Non-Small-Cell Lung, MESH: MAP Kinase Signaling System, MESH : bcl-2-Associated X Protein, MESH : Humans, Staurosporine, MESH : Glycoproteins, MESH: Lung Neoplasms, Androstadienes, MESH: Proto-Oncogene Proteins c-bcl-2, chemistry, Carrier Proteins, MESH: Flavonoids, MESH : Apoptosis, MESH: Signal Transduction, MESH : Staurosporine, MESH: Insulin-Like Growth Factor I, MESH : Models, Biological, MESH : Proto-Oncogene Proteins c-bcl-2, MESH : Culture Media, Serum-Free, chemistry.chemical_compound, Carcinoma, Non-Small-Cell Lung, Insulin-Like Growth Factor I, Protein Kinase C, Phosphoinositide-3 Kinase Inhibitors, bcl-2-Associated X Protein, MESH: Naphthalenes, Isoenzymes, Proto-Oncogene Proteins c-bcl-2, MESH: Enzyme Inhibitors, MESH: Isoenzymes, bcl-Associated Death Protein, Signal Transduction, medicine.drug, EGF Family of Proteins, MESH: Cell Line, Tumor, MESH: Glycoproteins, MESH : Androstadienes, MESH : MAP Kinase Signaling System, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Amphiregulin, Models, Biological, Cell Line, Tumor, MESH : Naphthalenes, medicine, MESH: bcl-2-Associated X Protein, Calphostin, MESH : Protein Kinase C, MESH: Intercellular Signaling Peptides and Proteins, MESH : Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Flavonoids, MESH : Signal Transduction, MESH : Enzyme Inhibitors, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH: Models, Biological, MESH: 1-Phosphatidylinositol 3-Kinase, Cell Biology, MESH: Protein Kinase C, MESH: Androstadienes, MESH: Staurosporine, biology.protein, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

International audience; Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) are growth factors known to promote non-small cell lung cancer (NSCLC) survival. We have previously published that 1) AR and IGF1, secreted by H358 NSCLC cells, cooperate to protect those cells and H322 NSCLC cells from serum-starved apoptosis; 2) H358 cells resist Bax-induced apoptosis through an inhibition of Bax conformational change. We show here that the antiapoptotic activity of the AR/IGF1 combination is specifically abolished by the PKC inhibitors calphostin C and staurosporine, but not by the MAPK and phosphatidylinositol 3-kinase inhibitors PD98059 and wortmannin, suggesting the involvement of a PKC-dependent and MAPK- and phosphatidylinositol 3-kinase-independent survival pathway. The PKCdelta inhibitor rottlerin restores apoptosis induced by serum deprivation. In addition, phosphorylation of PKCdelta and PKCzeta/lambda, but not of PKCalpha/beta(II), increases in serum-starved H358 cells and in H322 cells treated with an AR/IGF1 combination and is blocked by calphostin C. The combination of AR and IGF1 increases p90(rsk) and Bad phosphorylation as well as inhibiting the conformational change of Bax by a PKC-dependent mechanism. Finally, PKCdelta, PKCzeta, or p90(rsk) small interfering RNAs block the antiapoptotic activity of AR/IGF1 combination but have no effect on partial apoptosis inhibition observed with each factor used alone. Constitutively active PKC expression inhibits serum deprivation-induced apoptosis, whereas a catalytically inactive form of p90(rsk) restores it. Thus, AR and IGF1 cooperate to prevent apoptosis by activating a specific PKC-p90(rsk)-dependent pathway, which leads to Bad and Bax inactivation. This signaling pathway is different to that used by single factor.

Published
2005
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2. Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level

Author

Delphine Merino, Eric Solary, Guillaume Jacquemin, Philippe Saas, Najoua Lalaoui, Elisabetta Iessi, Olivier Micheau, Carmen Garrido, Bruno Chauffert, Florence Bouyer, David Lanneau, Virginie Granci, Alexandre Morizot, Mort Cellulaire et Cancer, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Plateforme de Biomonitoring, Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), INCa (Polynom174), ANR-06-JCJC-0103,TRAILCHIM,TRAIL et chimiothérapies anticancéreuses(2006), European Project, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), ANR-06-JCJC-0103, ANR--07-PCV-0031,ANR-06-JCJC-0103, ANR--07-PCV-0031, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC)

Subjects
MESH: CASP8 and FADD-Like Apoptosis Regulating Protein, MESH : Antineoplastic Combined Chemotherapy Protocols, CASP8 and FADD-Like Apoptosis Regulating Protein, TRAIL, Apoptosis, MESH : Models, Biological, Mitochondrion, MESH : RNA, Small Interfering, MESH: Caspase 8, TNF-Related Apoptosis-Inducing Ligand, MESH : TNF-Related Apoptosis-Inducing Ligand, MESH : Tumor Necrosis Factor Decoy Receptors, 0302 clinical medicine, RNA interference, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, MESH: RNA, Small Interfering, MESH: Neoplasms, RNA, Small Interfering, Receptor, Sensitization, Caspase 8, 0303 health sciences, MESH : Caspase 8, MESH: Drug Resistance, Neoplasm, 3. Good health, Cell biology, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH : Drug Resistance, Neoplasm, medicine.anatomical_structure, 030220 oncology & carcinogenesis, RNA Interference, MESH : GPI-Linked Proteins, MESH: TNF-Related Apoptosis-Inducing Ligand, Death Domain Receptor Signaling Adaptor Proteins, Programmed cell death, MESH: Cell Line, Tumor, c-FLIP, MESH: RNA Interference, Biology, GPI-Linked Proteins, Models, Biological, 03 medical and health sciences, Cell Line, Tumor, Receptors, Tumor Necrosis Factor, Member 10c, medicine, TRAIL-R4, Humans, cancer, Chemotherapy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Receptors, TNF-Related Apoptosis-Inducing Ligand, MESH : Receptors, TNF-Related Apoptosis-Inducing Ligand, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology, Original Paper, MESH: Humans, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH : Humans, MESH: Models, Biological, MESH : CASP8 and FADD-Like Apoptosis Regulating Protein, Cell Biology, MESH: Tumor Necrosis Factor Decoy Receptors, MESH : Neoplasms, Receptors, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor Decoy Receptors, Drug Resistance, Neoplasm, MESH : RNA Interference, MESH: GPI-Linked Proteins, MESH : Apoptosis, MESH : Death Domain Receptor Signaling Adaptor Proteins, MESH: Death Domain Receptor Signaling Adaptor Proteins
Abstract

International audience; TNF-related apoptosis-inducing ligand or Apo2L (Apo2L/TRAIL) is a promising anti-cancer drug owing to its ability to trigger apoptosis by binding to TRAIL-R1 or TRAIL-R2, two membrane-bound receptors that are often expressed by tumor cells. TRAIL can also bind non-functional receptors such as TRAIL-R4, but controversies still exist regarding their potential to inhibit TRAIL-induced apoptosis. We show here that TRAIL-R4, expressed either endogenously or ectopically, inhibits TRAIL-induced apoptosis. Interestingly, the combination of chemotherapeutic drugs with TRAIL restores tumor cell sensitivity to apoptosis in TRAIL-R4-expressing cells. This sensitization, which mainly occurs at the death-inducing signaling complex (DISC) level, through enhanced caspase-8 recruitment and activation, is compromised by c-FLIP expression and is independent of the mitochondria. Importantly, TRAIL-R4 expression prevents TRAIL-induced tumor regression in nude mice, but tumor regression induced by TRAIL can be restored with chemotherapy. Our results clearly support a negative regulatory function for TRAIL-R4 in controlling TRAIL signaling, and unveil the ability of TRAIL-R4 to cooperate with c-FLIP to inhibit TRAIL-induced cell death.

Published
2010
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3. Profiles and seasonal distribution of airborne fungi in indoor and outdoor environments at a French hospital

Author

B. Cuisenier, Frédéric Dalle, Nathalie Sixt, Alain Bonnin, Gérard Couillault, Claire Cachia, Stéphanie Valvin, O. Vagner, Vitalie Fourquenet, Marc Sautour, Céline Calinon, Denis Caillot, Kusum Paul, Alix Maurel, C. L’Ollivier, Serge Aho, Laboratoire Interactions Muqueuses Agents Transmissibles ( LIMA ), Université de Bourgogne ( UB ), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Santé - STIC, Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Interactions Muqueuses Agents Transmissibles (LIMA), Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Veterinary medicine, Environmental Engineering, Seasonal distribution, Air Microbiology, 010501 environmental sciences, 01 natural sciences, 03 medical and health sciences, Bjerkandera adusta, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, medicine, Environmental Chemistry, Hospital Design and Construction, Waste Management and Disposal, Air quality index, Airborne fungi Outdoor and indoor air Hospital Haematology units Seasonal variations Aspergillus, 0105 earth and related environmental sciences, 0303 health sciences, Aspergillus, biology, 030306 microbiology, Ecology, Fungi, Fungi imperfecti, Seasonality, biology.organism_classification, medicine.disease, Pollution, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Air Pollution, Indoor, Penicillium, Particulate Matter, France, Seasons, Environmental Monitoring, Cladosporium
Abstract

International audience; A one-year prospective survey of fungal air contamination was conducted in outdoor air and inside two haematological units of a French hospital. Air was sampled with a portable Air System Impactor. During this period of survey, the mean viable fungal load was 122.1 cfu/m(3) in outdoor air samples, and 4.1 and 3.9 cfu/m(3) in samples from adult and pediatric haematology units, respectively. In outdoor samples, Cladosporium was the dominant genus (55%) while in the clinical units, Penicillium sp. (23 to 25%), Aspergillus sp. (15 to 23%) and Bjerkandera adusta (11 to 13%) were the most frequently recovered airborne fungi. The outdoor fungal load was far higher in autumn (168 cfu/m(3)), spring (110 cfu/m(3)) and summer (138 cfu/m(3)) than in winter (49 cfu/m(3)). In indoor air, fungal concentrations were significantly lower in winter (2.7 to 3.1 cfu/m(3)) than in summer (4.2 to 5.0 cfu/m(3)) in both haematology units. In the outdoor environment, Penicillium sp. and Aspergillus sp. were more abundant in winter while the levels of Cladosporium were lowest during this season. In the haematological units, the presence of Aspergillus sp. was stable during the year (close to 20%), Bjerkandera sp. was particularly abundant in winter (close to 30%); levels of Penicillium sp. were highest in autumn while levels of Cladosporium sp. were highest in spring and summer.

Published
2009
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4. A prospective survey of air and surface fungal contamination in a medical mycology laboratory at a tertiary care university hospital

Author

O. Vagner, Alain Bonnin, Elsa Salome, Serge Aho, Véronique Fricker-Pap, Olivier Fontaneau, Isabelle Chovelon, Coralie L'Ollivier, Emilie Enderlin, Frédéric Dalle, Claire Olivieri, Marc Sautour, Nathalie Sixt, Claire Cachia, Laboratoire Interactions Muqueuses Agents Transmissibles ( LIMA ), Université de Bourgogne ( UB ), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Santé - STIC, Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Interactions Muqueuses Agents Transmissibles (LIMA), Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
medicine.medical_specialty, Veterinary medicine, Epidemiology, Fungal contamination, Colony Count, Microbial, Context (language use), Mycology, Sabouraud agar, Hospitals, University, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Environmental Microbiology, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Air quality index, Prospective survey, 0303 health sciences, Airborne fungi indoor air Hospital Laboratory of Mycology Aspergillus Shewhart graphic charts, 030306 microbiology, business.industry, Health Policy, Fungi, Public Health, Environmental and Occupational Health, Contamination, Laboratories, Hospital, 3. Good health, Surgery, Transplantation, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, chemistry, business
Abstract

International audience; BACKGROUND: Invasive filamentous fungi infections resulting from inhalation of mold conidia pose a major threat in immunocompromised patients. The diagnosis is based on direct smears, cultural symptoms, and culturing fungi. Airborne conidia present in the laboratory environment may cause contamination of cultures, resulting in false-positive diagnosis. Baseline values of fungal contamination in a clinical mycology laboratory have not been determined to date. METHODS: A 1-year prospective survey of air and surface contamination was conducted in a clinical mycology laboratory during a period when large construction projects were being conducted in the hospital. Air was sampled with a portable air system impactor, and surfaces were sampled with contact Sabouraud agar plates. The collected data allowed the elaboration of Shewhart graphic charts. RESULTS: Mean fungal loads ranged from 2.27 to 4.36 colony forming units (cfu)/m(3) in air and from 0.61 to 1.69 cfu/plate on surfaces. CONCLUSIONS: Strict control procedures may limit the level of fungal contamination in a clinical mycology laboratory even in the context of large construction projects at the hospital site. Our data and the resulting Shewhart graphic charts provide baseline values to use when monitoring for inappropriate variations of the fungal contamination in a mycology laboratory as part of a quality assurance program. This is critical to the appropriate management of the fungal risk in hematology, cancer and transplantation patients.

Published
2009
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5. Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer

Author

Jean-Pierre Kantelip, Xavier Pivot, Bruno Chauffert, Emmanuel Guardiola, Delphine Delroeux, Marielle Combe, Bernard Royer, Guillaume Hoizey, Bruno Heyd, Damien Montange, Laboratoire de Pharmacologie Clinique et Toxicologie [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Service de chirurgie viscérale et digestive - Unité de transplantation hépatique, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Service d'oncologie Médicale, Département d'Anesthésie, Université de Reims Champagne-Ardenne ( URCA ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Saas, Philippe, Laboratoire de Pharmacologie Clinique et Toxicologie [CHRU Besancon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Oncologie Médicale [CHRU Besançon], Université de Reims Champagne-Ardenne (URCA), and Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cancer Research, medicine.medical_treatment, FIGO Stage IIIC, MESH : Aged, Toxicology, MESH : Antineoplastic Agents, Phytogenic, Carboplatin, Intraoperative Period, 0302 clinical medicine, MESH: Carboplatin, Medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Pharmacology (medical), Infusions, Parenteral, MESH : Neoplasm Staging, MESH : Female, 030212 general & internal medicine, Ovarian Neoplasms, MESH: Aged, MESH: Middle Aged, Area under the curve, MESH : Protein Binding, MESH: Neoplasm Staging, Middle Aged, MESH : Adult, Debulking, 3. Good health, MESH: Ovarian Neoplasms, MESH : Antineoplastic Agents, MESH : Infusions, Parenteral, Oncology, 030220 oncology & carcinogenesis, Area Under Curve, MESH : Paclitaxel, MESH : Carboplatin, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Intraoperative Period, medicine.drug, Protein Binding, Adult, medicine.medical_specialty, Paclitaxel, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Antineoplastic Agents, Phytogenic, Urology, Antineoplastic Agents, MESH : Cisplatin, 03 medical and health sciences, Pharmacokinetics, Humans, MESH: Protein Binding, MESH : Middle Aged, MESH: Paclitaxel, Aged, Neoplasm Staging, Pharmacology, Cisplatin, MESH: Intraoperative Period, Chemotherapy, MESH: Humans, business.industry, MESH : Ovarian Neoplasms, MESH : Humans, Cancer, MESH: Adult, medicine.disease, Antineoplastic Agents, Phytogenic, Surgery, MESH: Infusions, Parenteral, MESH: Cisplatin, MESH: Antineoplastic Agents, MESH: Area Under Curve, MESH : Area Under Curve, business, Ovarian cancer, MESH: Female
Abstract

International audience; Ovarian cancer is the leading cause of gynecological cancer-related death in Western countries. The present treatment standards for ovarian cancer are based on the association of debulking surgery with platinum-based chemotherapy. Another strategy that could be further investigated is intraperitoneal chemotherapy (IP). We previously described that the 2-h administration of intraoperative IP cisplatin did not reach satisfactory concentrations. In the present study, we present the results of a pharmacokinetic analysis performed after two consecutive 1-h IP 30 mg/l cisplatin administrations. Twenty-seven patients with advanced epithelial cancer classified FIGO stage IIIC were included in the study. Blood and IP samples were taken over a 24-h period, during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentration levels were analyzed. Biological and clinical toxicities were also recorded. With this strategy, IP Pt concentrations stayed above the target concentration (10 mg/l) for a satisfactory length of time. The serum Pt concentrations were higher than those observed with the "one-bath" protocol and they induced the occurrence of recoverable renal toxicities (3 grade 1, 7 grade 2 and 4 grade 3). The best predictive parameter for renal failure was the total Pt 24-h Area Under the Curve (AUC) with a threshold value of 25 mg h/l RR = 0.31 (95% CI 0.13 - 0.49, P < 0.01). Administration of an increased amount of cisplatin is feasible and a satisfactory level of IP Pt concentrations is obtained. However, this improvement is associated with an increase in serum Pt levels and resulting renal toxicities. An attractive solution would be to decrease Pt transfer from peritoneum to bloodstream. A phase 1 study using intraoperative IP epinephrine in order to decrease this transfer is presently being carried out.

Published
2008
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6. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner

Author

Jacky Bernard, Antônio C. Freitas, Jean-Yves Blay, Caroline Flament, Orianne Wagner-Ballon, Laurence Zitvogel, Cédric Ménard, A. Lecesne, Magali Terme, T. Tursz, Caroline Robert, Bernard Escudier, William Vainchencker, Eric Vivier, Claude Capron, Julien Taieb, Sophie Caillat-Zucman, François Ghiringhelli, Sophie Novault, Nathalie Chaput, Pierre E. Puig, François Martin, Rôle des cellules dendritiques dans la régulation des effecteurs de l'immunité antitumorale, Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hematopoïèse et Cellules Souches ( U362 ), 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 ), Centre Jean Godineau, Etablissement Français du Sang, Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Biologie des Populations Lymphocytaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematopoïèse et Cellules Souches (U362), 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), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH : Cytokines, MESH: Flow Cytometry, MESH : Immunity, Natural, MESH: T-Ly, Lymphocyte Activation, T-Lymphocytes, Regulatory, Mice, Interleukin 21, 0302 clinical medicine, T-Lymphocyte Subsets, Transforming Growth Factor beta, Neoplasms, MESH : Receptors, Immunologic, MESH : Cell Proliferation, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Neoplasms, IL-2 receptor, Receptors, Immunologic, 0303 health sciences, MESH: Cytokines, hemic and immune systems, Flow Cytometry, Natural killer T cell, 3. Good health, Cell biology, Killer Cells, Natural, medicine.anatomical_structure, NK Cell Lectin-Like Receptor Subfamily K, Interleukin 12, Cytokines, Receptors, Natural Killer Cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, France, MESH : Killer Cells, Natural, MESH : Cytotoxicity Tests, Immunologic, MESH: Killer Cells, Natural, MESH: Cell Line, Tumor, MESH : Flow Cytometry, Immunology, chemical and pharmacologic phenomena, MESH: Cytotoxicity Tests, Immunologic, MESH : Mice, Inbred C57BL, Biology, Article, Natural killer cell, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Cell Line, Tumor, MESH: Cell Proliferation, MESH : Mice, medicine, Animals, Humans, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH : France, MESH: Mice, MESH: Receptors, Immunologic, MESH : Lymphocyte Activation, Cell Proliferation, 030304 developmental biology, MESH: Immunity, Natural, Lymphokine-activated killer cell, MESH: Humans, MESH : Cell Line, Tumor, MESH : Humans, Cytotoxicity Tests, Immunologic, NKG2D, MESH : T-Ly, MESH : Neoplasms, Immunity, Innate, Mice, Inbred C57BL, MESH: France, MESH : Animals, 030215 immunology
Abstract

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

Published
2007
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7. Caspase-8 prevents sustained activation of NF-kappaB in monocytes undergoing macrophagic differentiation.: Caspase-8 in the macrophage differentiation

Author

Rébé, Cédric, Cathelin, Séverine, Launay, Sophie, Filomenko, Rodolphe, Prévotat, Laurent, L'Ollivier, Coralie, Gyan, Emmanuel, Micheau, Olivier, Grant, Steven, Dubart-Kupperschmitt, Anne, Fontenay, Michaëla, Solary, Eric, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - STIC, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Department of Pharmacology and biochemistry, Virginia Commonwealth University (VCU), This study was supported by a special grant from the Ligue Nationale Contre le Cancer to ES (équipe labélisée) and a grant from the Direction Régionale de la Recherche Clinique de l'Assistance Publique des Hôpitaux de Paris to MF. SL, SC and RF were sustained by the Ligue Nationale Contre le Cancer, CR by the Association pour la Recherche contre le Cancer and EG by the Inserm., and Micheau, Olivier

Subjects
MESH: Cell Differentiation, MESH: RNA-Binding Proteins, MESH: Cell Line, Tumor, MESH: Humans, MESH: Macrophage Colony-Stimulating Factor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Macrophages, MESH: NF-kappa B, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Fas-Associated Death Domain Protein, MESH: Monocytes, MESH: Caspase 8, MESH: Nuclear Pore Complex Proteins
Abstract

Caspases have demonstrated several nonapoptotic functions including a role in the differentiation of specific cell types. Here, we show that caspase-8 is the upstream enzyme in the proteolytic caspase cascade whose activation is required for the differentiation of peripheral-blood monocytes into macrophages. On macrophage colony-stimulating factor (M-CSF) exposure, caspase-8 associates with the adaptor protein Fas-associated death domain (FADD), the serine/threonine kinase receptor-interacting protein 1 (RIP1) and the long isoform of FLICE-inhibitory protein FLIP. Overexpression of FADD accelerates the differentiation process that does not involve any death receptor. Active caspase-8 cleaves RIP1, which prevents sustained NF-kappaB activation, and activates downstream caspases. Together these data identify a role for caspase-8 in monocytes undergoing macrophagic differentiation, that is, the enzyme activated in an atypical complex down-regulates NF-kappaB activity through RIP1 cleavage.

Published
2007
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8. Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis

Author

Niels Bovenschen, J. Tschopp, Pascal Schneider, Roel Broekhuizen, Razi Quadir, J A Kummer, Olivier Micheau, C E Hack, Merel C. M. Strik, Landsteiner Laboratory, Department of Biochemistry, Université de Lausanne ( UNIL ), Department of Pathology, VU University Medical Center [Amsterdam], University Medical Center Utrecht, Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Immunopathology, Sanquin Research at CLB and Landsteiner Laboratory-Academical Medical Center, Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), University Medical Center [Utrecht], Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), and Micheau, Olivier

Subjects
Programmed cell death, Fas Ligand Protein, Serine Proteinase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Apoptosis, Serpin, Ligands, Models, Biological, TNF-Related Apoptosis-Inducing Ligand, 03 medical and health sciences, Mice, 0302 clinical medicine, Transduction, Genetic, Cell Line, Tumor, Animals, Apoptosis/physiology, Caspase 10/metabolism, Caspase 3/metabolism, Caspase 8/metabolism, Fas Ligand Protein/physiology, Humans, Poly(ADP-ribose) Polymerases/metabolism, Protein Processing, Post-Translational, Receptors, Death Domain/physiology, Recombinant Proteins/genetics, Recombinant Proteins/metabolism, Serine Proteinase Inhibitors/genetics, Serine Proteinase Inhibitors/physiology, Serpins/genetics, Serpins/physiology, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand/physiology, Tumor Necrosis Factor-alpha/physiology, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Caspase 10, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Caspase, Serpins, 030304 developmental biology, Inhibitor of apoptosis domain, 0303 health sciences, Caspase 8, biology, Caspase 3, Tumor Necrosis Factor-alpha, Intrinsic apoptosis, Cell Biology, Receptors, Death Domain, Molecular biology, Protease inhibitor (biology), Recombinant Proteins, Cell biology, XIAP, 030220 oncology & carcinogenesis, biology.protein, Poly(ADP-ribose) Polymerases, medicine.drug
Abstract

Apoptosis is a highly controlled process, whose triggering is associated with the activation of caspases. Apoptosis can be induced via a subgroup of the tumor necrosis factor (TNF) receptor superfamily, which recruit and activate pro-caspase-8 and -10. Regulation of apoptosis is achieved by several inhibitors, including c-FLICE-inhibitory protein, which prevents apoptosis by inhibiting the pro-apoptotic activation of upstream caspases. Here we show that the human intracellular serine protease inhibitor (serpin), protease inhibitor 9 (PI9), inhibits TNF-, TNF-related apoptosis-inducing ligand- and Fas ligand-mediated apoptosis in certain TNF-sensitive cell lines. The reactive center P1 residue of PI9 was required for this inhibition since PI9 harboring a Glu --> Ala mutation in its reactive center failed to impair death receptor-induced cell death. This suggests a classical serpin-protease interaction. Indeed, PI9 inhibited apoptotic death by directly interacting with the intermediate active forms of caspase-8 and -10. This indicates that PI9 can regulate pro-apoptotic apical caspases.

Published
2007
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9. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates

Author

Cyril Boyault, Benoit Gilquin, Yu Zhang, Carmen Garrido, Cécile Caron, Patrick Matthias, Saadi Khochbin, So Hee Kwon, Claire Vourc'h, Sabrina Fritah, Tso-Pang Yao, Souchier, Catherine, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology and Cancer Biology, Duke University [Durham], INSERM U823, équipe 10 (Stress et Dynamique de l'Organisation du Génome), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U823, équipe 6 (Epigénétique et Signalisation Cellulaire), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Friedrich Miescher Institute for Biomedical Research ( FMI ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Duke university [Durham], and Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
Protein Folding, MESH : Transcription Factors, MESH: 3T3 Cells, Leupeptins, Cell Cycle Proteins, MESH: Tubulin, Protein aggregation, Histone Deacetylase 6, Mice, MESH : Cell Cycle Proteins, 0302 clinical medicine, Heat Shock Transcription Factors, MESH : Leupeptins, Tubulin, Valosin Containing Protein, MESH: Animals, Nuclear protein, HSF1, MESH: HSP70 Heat-Shock Proteins, MESH : Ubiquitin, Adenosine Triphosphatases, 0303 health sciences, MESH : Histone Deacetylases, Nuclear Proteins, MESH : Protein Binding, Acetylation, 3T3 Cells, MESH: Transcription Factors, MESH : Tubulin, MESH : HSP90 Heat-Shock Proteins, MESH : Heat-Shock Response, Hsp90, Cell biology, DNA-Binding Proteins, Aggresome, 030220 oncology & carcinogenesis, MESH : DNA-Binding Proteins, MESH: Molecular Chaperones, MESH: Acetylation, MESH : Protein Folding, MESH : 3T3 Cells, Protein Binding, Research Paper, MESH: Ubiquitin, MESH: Protein Folding, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH : Acetylation, Histone Deacetylases, 03 medical and health sciences, MESH: Cell Cycle Proteins, MESH : Mice, Genetics, MESH: Adenosine Triphosphatases, MESH: HSP90 Heat-Shock Proteins, Animals, MESH: Protein Binding, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Cell Cycle Protein, Transcription factor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH : Adenosine Triphosphatases, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Ubiquitin, MESH : Molecular Chaperones, MESH : Nuclear Proteins, MESH : HSP70 Heat-Shock Proteins, MESH: Leupeptins, HDAC6, MESH: Histone Deacetylases, MESH: Heat-Shock Response, biology.protein, MESH : Animals, MESH: Nuclear Proteins, Heat-Shock Response, MESH: DNA-Binding Proteins, Molecular Chaperones, Transcription Factors, Developmental Biology
Abstract

International audience; A cellular defense mechanism counteracts the deleterious effects of misfolded protein accumulation by eliciting a stress response. The cytoplasmic deacetylase HDAC6 (histone deacetylase 6) was previously shown to be a key element in this response by coordinating the clearance of protein aggregates through aggresome formation and their autophagic degradation. Here, for the first time, we demonstrate that HDAC6 is involved in another crucial cell response to the accumulation of ubiquitinated protein aggregates, and unravel its molecular basis. Indeed, our data show that HDAC6 senses ubiquitinated cellular aggregates and consequently induces the expression of major cellular chaperones by triggering the dissociation of a repressive HDAC6/HSF1 (heat-shock factor 1)/HSP90 (heat-shock protein 90) complex and a subsequent HSF1 activation. HDAC6 therefore appears as a master regulator of the cell protective response to cytotoxic protein aggregate formation.

Published
2007
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10. Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2

Author

Najoua Lalaoui, Alexandre Morizot, Olivier Micheau, Delphine Merino, Eric Solary, Pascal Schneider, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université de Bourgogne (UB), Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), INCa PL098, Ligue Nationale contre le Cancer, Conseil Régional de Bourgogne, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Université de Bourgogne ( UB ), Biochemistry Department, Université de Lausanne ( UNIL ), Micheau, Olivier, and Université de Lausanne = University of Lausanne (UNIL)

Subjects
MESH : Hela Cells, MESH: Membrane Glycoproteins, MESH: Membrane Microdomains, Decoy Receptor 1, Apoptosis, MESH : Membrane Glycoproteins, Receptors, Tumor Necrosis Factor, TNF-Related Apoptosis-Inducing Ligand, MESH : TNF-Related Apoptosis-Inducing Ligand, Jurkat Cells, 0302 clinical medicine, MESH : Tumor Necrosis Factor Decoy Receptors, MESH: Jurkat Cells, Decoy receptors, Receptor, Cells, Cultured, MESH : Jurkat Cells, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, Membrane Glycoproteins, MESH : Protein Binding, Articles, MESH : Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Cell biology, 030220 oncology & carcinogenesis, Caspases, Death-inducing signaling complex, Apoptosis/drug effects, Apoptosis Regulatory Proteins/antagonists & inhibitors, Apoptosis Regulatory Proteins/pharmacology, Caspases/metabolism, Death Domain Receptor Signaling Adaptor Proteins, Enzyme Activation/drug effects, GPI-Linked Proteins, HeLa Cells, Humans, Membrane Glycoproteins/antagonists & inhibitors, Membrane Glycoproteins/pharmacology, Membrane Microdomains/drug effects, Protein Binding/drug effects, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor/metabolism, Tumor Necrosis Factor Decoy Receptors, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Tumor Necrosis Factor-alpha/pharmacology, MESH : Apoptosis Regulatory Proteins, MESH: TNF-Related Apoptosis-Inducing Ligand, Protein Binding, MESH: Cells, Cultured, MESH: Enzyme Activation, Biology, MESH: Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, 03 medical and health sciences, Membrane Microdomains, Cell surface receptor, MESH : Cells, Cultured, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptors, Tumor Necrosis Factor, Member 10c, MESH: Protein Binding, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Receptors, TNF-Related Apoptosis-Inducing Ligand, MESH : Receptors, TNF-Related Apoptosis-Inducing Ligand, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Death domain, MESH: Caspases, MESH: Humans, Tumor Necrosis Factor-alpha, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH : Humans, Cell Biology, MESH: Receptors, Tumor Necrosis Factor, MESH: Tumor Necrosis Factor Decoy Receptors, MESH : Receptors, Tumor Necrosis Factor, Enzyme Activation, MESH: Hela Cells, MESH: Tumor Necrosis Factor-alpha, MESH : Membrane Microdomains, MESH : Caspases, Apoptosis Regulatory Proteins, MESH : Enzyme Activation, MESH : Apoptosis, MESH : Death Domain Receptor Signaling Adaptor Proteins, MESH: Death Domain Receptor Signaling Adaptor Proteins
Abstract

International audience; Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that induces cancer cell death by apoptosis with some selectivity. TRAIL-induced apoptosis is mediated by the transmembrane receptors death receptor 4 (DR4) (also known as TRAIL-R1) and DR5 (TRAIL-R2). TRAIL can also bind decoy receptor 1 (DcR1) (TRAIL-R3) and DcR2 (TRAIL-R4) that fail to induce apoptosis since they lack and have a truncated cytoplasmic death domain, respectively. In addition, DcR1 and DcR2 inhibit DR4- and DR5-mediated, TRAIL-induced apoptosis and we demonstrate here that this occurs through distinct mechanisms. While DcR1 prevents the assembly of the death-inducing signaling complex (DISC) by titrating TRAIL within lipid rafts, DcR2 is corecruited with DR5 within the DISC, where it inhibits initiator caspase activation. In addition, DcR2 prevents DR4 recruitment within the DR5 DISC. The specificity of DcR1- and DcR2-mediated TRAIL inhibition reveals an additional level of complexity for the regulation of TRAIL signaling.

Published
2006
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11. E2F1 induces apoptosis and sensitizes human lung adenocarcinoma cells to death-receptor-mediated apoptosis through specific downregulation of c-FLIP(short): E2F1 targets c-FLIPS to induce apoptosis

Author

Salon, Caroline, Eymin, Béatrice, Micheau, Olivier, Chaperot, Laurence, Plumas, Joël, Brambilla, Christian, Brambilla, Elisabeth, Gazzeri, Sylvie, Groupe de Recherche Sur Le Cancer du Poumon : Bases Moléculaires de la Progression Tumorale, Dépistage et Thérapie Génique, Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), and Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)

Subjects
endocrine system, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, biological phenomena, cell phenomena, and immunity
Abstract

International audience; E2F1 is a transcription factor that plays a well-documented role during S phase progression and apoptosis. We had previously postulated that the low level of E2F1 in primary lung adenocarcinoma contributes to their carcinogenesis. Here, we show that E2F1 triggers apoptosis in various lung adenocarcinoma cell lines by a mechanism involving the specific downregulation of the cellular FLICE-inhibitory protein short, leading to caspase-8 activation at the death-inducing signaling complex. Importantly, we also provide evidence that E2F1 sensitizes tumor as well as primary cells to apoptosis mediated by FAS ligand or tumor necrosis factor-related apoptosis-inducing ligand, and enhances the cytotoxic effect of T lymphocytes against tumor cells. Finally, we describe the specific overexpression of c-FLIP(S) in human lung adenocarcinomas with low level of E2F1. Overall, our data identify E2F1 as a critical determinant of the cellular response to death-receptor-mediated apoptosis, and suggest that its downregulation contributes to the immune escape of lung adenocarcinoma tumor cells.

Published
2006
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12. E2F1 induces apoptosis and sensitizes human lung adenocarcinoma cells to death-receptor-mediated apoptosis through specific downregulation of c-FLIP(short)

Author

Elisabeth Brambilla, Laurence Chaperot, Christian Brambilla, Olivier Micheau, Joel Plumas, Sylvie Gazzeri, Caroline Salon, Beatrice Eymin, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Michallon, INSERM U823, équipe 2 (Bases Moléculaires de la Progression des Cancers du Poumon), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Etablissement Français du Sang Rhône-Alpes, EFS, Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Salas, Danielle

Subjects
MESH: CASP8 and FADD-Like Apoptosis Regulating Protein, MESH : RNA, Messenger, Lung Neoplasms, MESH : DNA, MESH : Cytotoxicity, Immunologic, MESH: Membrane Glycoproteins, CASP8 and FADD-Like Apoptosis Regulating Protein, Apoptosis, MESH : Blotting, Western, MESH : Fluorescent Antibody Technique, Indirect, MESH: Down-Regulation, MESH : E2F1 Transcription Factor, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, TNF-Related Apoptosis-Inducing Ligand, MESH : Adenocarcinoma, 0302 clinical medicine, Cytotoxic T cell, Fluorescent Antibody Technique, Indirect, 0303 health sciences, Membrane Glycoproteins, MESH : Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, MESH: Tumor Necrosis Factors, Cell biology, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Caspases, Adenocarcinoma, Tumor necrosis factor alpha, MESH: TNF-Related Apoptosis-Inducing Ligand, endocrine system, MESH: Enzyme Activation, MESH : Gene Expression Regulation, Neoplastic, Blotting, Western, Down-Regulation, MESH : T-Lymphocytes, Cytotoxic, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Blotting, Western, Humans, MESH : Lung Neoplasms, RNA, Messenger, Molecular Biology, MESH: Humans, MESH: Caspases, Tumor Necrosis Factor-alpha, MESH : Humans, DNA, medicine.disease, MESH: Lung Neoplasms, Enzyme Activation, MESH: Tumor Necrosis Factor-alpha, Apoptosis Regulatory Proteins, MESH : Apoptosis, T-Lymphocytes, Cytotoxic, Cytotoxicity, Immunologic, MESH : Membrane Glycoproteins, MESH : Fas Ligand Protein, MESH: Caspase 8, Fas ligand, MESH : Down-Regulation, MESH : TNF-Related Apoptosis-Inducing Ligand, MESH: Reverse Transcriptase Polymerase Chain Reaction, E2F1, MESH : Tumor Necrosis Factor-alpha, Caspase 8, MESH : Caspase 8, Reverse Transcriptase Polymerase Chain Reaction, MESH: DNA, MESH: Gene Expression Regulation, Neoplastic, MESH: E2F1 Transcription Factor, Tumor Necrosis Factors, biological phenomena, cell phenomena, and immunity, MESH : Apoptosis Regulatory Proteins, Programmed cell death, MESH: Cell Line, Tumor, Fas Ligand Protein, MESH : Tumor Necrosis Factors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Downregulation and upregulation, MESH : Intracellular Signaling Peptides and Proteins, MESH: Intracellular Signaling Peptides and Proteins, Cell Line, Tumor, medicine, MESH: Fluorescent Antibody Technique, Indirect, MESH: Cytotoxicity, Immunologic, 030304 developmental biology, MESH: RNA, Messenger, MESH : Cell Line, Tumor, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH: Adenocarcinoma, Cell Biology, MESH : CASP8 and FADD-Like Apoptosis Regulating Protein, MESH: Fas Ligand Protein, Cancer research, MESH : Caspases, MESH : Enzyme Activation, MESH: T-Lymphocytes, Cytotoxic, E2F1 Transcription Factor
Abstract

E2F1 is a transcription factor that plays a well-documented role during S phase progression and apoptosis. We had previously postulated that the low level of E2F1 in primary lung adenocarcinoma contributes to their carcinogenesis. Here, we show that E2F1 triggers apoptosis in various lung adenocarcinoma cell lines by a mechanism involving the specific downregulation of the cellular FLICE-inhibitory protein short, leading to caspase-8 activation at the death-inducing signaling complex. Importantly, we also provide evidence that E2F1 sensitizes tumor as well as primary cells to apoptosis mediated by FAS ligand or tumor necrosis factor-related apoptosis-inducing ligand, and enhances the cytotoxic effect of T lymphocytes against tumor cells. Finally, we describe the specific overexpression of c-FLIP(S) in human lung adenocarcinomas with low level of E2F1. Overall, our data identify E2F1 as a critical determinant of the cellular response to death-receptor-mediated apoptosis, and suggest that its downregulation contributes to the immune escape of lung adenocarcinoma tumor cells.

Published
2005
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13. Cooperation of amphiregulin and insulin-like growth factor-1 inhibits Bax- and Bad-mediated apoptosis via a protein kinase C-dependent pathway in non-small cell lung cancer cells

Author

Hurbin, Amandine, Coll, Jean-Luc, Dubrez-Daloz, Laurence, Mari, Bernard, Auberger, Patrick, Brambilla, Christian, Favrot, Marie-Christine, Groupe de Recherche Sur Le Cancer du Poumon : Bases Moléculaires de la Progression Tumorale, Dépistage et Thérapie Génique, Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiopathologie de la survie et de la mort cellulaire et infection virale, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR50-Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, MESH : Staurosporine, MESH: Insulin-Like Growth Factor I, MESH : Insulin-Like Growth Factor I, MESH : Models, Biological, MESH : Proto-Oncogene Proteins c-bcl-2, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Culture Media, Serum-Free, MESH : Flavonoids, MESH : 1-Phosphatidylinositol 3-Kinase, MESH : Isoenzymes, MESH: Naphthalenes, MESH: Culture Media, Serum-Free, MESH: Enzyme Inhibitors, MESH: Isoenzymes, MESH : bcl-Associated Death Protein, MESH : Carrier Proteins, MESH: Cell Line, Tumor, MESH: Glycoproteins, MESH : Androstadienes, MESH : MAP Kinase Signaling System, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Naphthalenes, MESH: bcl-Associated Death Protein, MESH: bcl-2-Associated X Protein, MESH : Lung Neoplasms, MESH : Protein Kinase C, MESH: Intercellular Signaling Peptides and Proteins, MESH : Intercellular Signaling Peptides and Proteins, MESH : Signal Transduction, MESH : Enzyme Inhibitors, MESH: Humans, MESH : Carcinoma, Non-Small-Cell Lung, MESH: MAP Kinase Signaling System, MESH : bcl-2-Associated X Protein, MESH : Cell Line, Tumor, MESH: Apoptosis, MESH : Humans, MESH: Models, Biological, MESH: 1-Phosphatidylinositol 3-Kinase, MESH: Protein Kinase C, MESH : Glycoproteins, MESH: Lung Neoplasms, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Androstadienes, MESH: Staurosporine, MESH: Flavonoids, MESH: Carcinoma, Non-Small-Cell Lung, MESH : Apoptosis
Abstract

International audience; Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) are growth factors known to promote non-small cell lung cancer (NSCLC) survival. We have previously published that 1) AR and IGF1, secreted by H358 NSCLC cells, cooperate to protect those cells and H322 NSCLC cells from serum-starved apoptosis; 2) H358 cells resist Bax-induced apoptosis through an inhibition of Bax conformational change. We show here that the antiapoptotic activity of the AR/IGF1 combination is specifically abolished by the PKC inhibitors calphostin C and staurosporine, but not by the MAPK and phosphatidylinositol 3-kinase inhibitors PD98059 and wortmannin, suggesting the involvement of a PKC-dependent and MAPK- and phosphatidylinositol 3-kinase-independent survival pathway. The PKCdelta inhibitor rottlerin restores apoptosis induced by serum deprivation. In addition, phosphorylation of PKCdelta and PKCzeta/lambda, but not of PKCalpha/beta(II), increases in serum-starved H358 cells and in H322 cells treated with an AR/IGF1 combination and is blocked by calphostin C. The combination of AR and IGF1 increases p90(rsk) and Bad phosphorylation as well as inhibiting the conformational change of Bax by a PKC-dependent mechanism. Finally, PKCdelta, PKCzeta, or p90(rsk) small interfering RNAs block the antiapoptotic activity of AR/IGF1 combination but have no effect on partial apoptosis inhibition observed with each factor used alone. Constitutively active PKC expression inhibits serum deprivation-induced apoptosis, whereas a catalytically inactive form of p90(rsk) restores it. Thus, AR and IGF1 cooperate to prevent apoptosis by activating a specific PKC-p90(rsk)-dependent pathway, which leads to Bad and Bax inactivation. This signaling pathway is different to that used by single factor.

Published
2005
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14. Controlling TRAIL-mediated caspase-3 activation

Author

Delphine Merino, Olivier Micheau, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Micheau, Olivier

Subjects
Cancer Research, T-Lymphocytes, MESH: Membrane Glycoproteins, Apoptosis, MESH : Membrane Glycoproteins, Jurkat cells, MESH : Proto-Oncogene Proteins c-bcl-2, TNF-Related Apoptosis-Inducing Ligand, MESH : TNF-Related Apoptosis-Inducing Ligand, 0302 clinical medicine, MESH: Caspase 3, MESH : Caspase 3, Caspase, bcl-2-Associated X Protein, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, Leukemia, Membrane Glycoproteins, biology, Caspase 3, MESH: Mitochondrial Proteins, MESH: Adenoviridae, Hematology, Mitochondria, 3. Good health, Cell biology, bcl-2 Homologous Antagonist-Killer Protein, Proto-Oncogene Proteins c-bcl-2, Oncology, Caspases, 030220 oncology & carcinogenesis, MESH : Proto-Oncogene Proteins, MESH : Mitochondria, MESH: Membrane Proteins, biological phenomena, cell phenomena, and immunity, MESH : Apoptosis Regulatory Proteins, MESH: TNF-Related Apoptosis-Inducing Ligand, Bcl-2 Homologous Antagonist-Killer Protein, Programmed cell death, MESH: Enzyme Activation, MESH: Mitochondria, Adenoviridae, Mitochondrial Proteins, 03 medical and health sciences, Bcl-2-associated X protein, Proto-Oncogene Proteins, MESH: Leukemia, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: bcl-2-Associated X Protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Adenoviridae, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Mitochondrial Proteins, 030304 developmental biology, Death domain, MESH : T-Lymphocytes, MESH: Caspases, MESH: Humans, Tumor Necrosis Factor-alpha, MESH : bcl-2-Associated X Protein, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH : Humans, MESH : Leukemia, Membrane Proteins, MESH : bcl-2 Homologous Antagonist-Killer Protein, Enzyme Activation, MESH: Proto-Oncogene Proteins, MESH: T-Lymphocytes, MESH: Proto-Oncogene Proteins c-bcl-2, MESH : Membrane Proteins, MESH: Tumor Necrosis Factor-alpha, biology.protein, MESH : Caspases, Apoptosis Regulatory Proteins, MESH : Enzyme Activation, MESH: bcl-2 Homologous Antagonist-Killer Protein, MESH : Apoptosis
Abstract

This commentary is addressed at the paper by Dr Jie and his co-workers in the current issue of Leukemia (‘Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells’). In this paper, the authors show the preferential use of Bax over Bak for the induction of mitochondrial apoptotic events in leukemic cell exposed to TRAIL 1. These findings are consistent with previous studies involving Bax in TRAIL-mediated apoptosis in the colon carcinoma cell line HCT116 2–4. The redundant function of Bak and Bax was initially demonstrated in lymphocytes subjected to various apoptotic stimuli 5–8. Hence, simultaneous Bax and Bak gene inactivation results in a profound effect on the control of lymphocyte survival upon growth factor or glucose deprivation 9. Whereas, Bak inactivation, alone, appears to have no effect, Bax inactivation, however, slightly affected lymphocyte survival 9. These data could therefore suggest that Bax and Bak may not be so redundant after all. Accordingly, the use of Jurkat clones deficient for both Bak and Bax by Jie and collaborators, revealed that Bax and Bak could exhibit differential functions, at least in the studied cell type system, as only Bax re-expression could restore caspase-3 processing and sensitization to TRAIL-induced cell death 1. Loss of function mutations of Bax are often found both in colon carcinomas 10 and in leukemias 11,12. Therefore, since both death domain containing receptors and chemotherapeutic agents may require Bax for the triggering of the apoptotic process 2,13, this information may be important for future cancer therapeutic approaches using TRAIL or TRAIL receptor agonists either alone or in combination with chemotherapeutic agents.

Published
2004
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15. Cellular FLICE-inhibitory protein: an attractive therapeutic target?

Author

Olivier Micheau, Mort cellulaire et cancer, Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), and Micheau, Olivier

Subjects
MESH: Neoplasm Proteins, MESH: Signal Transduction, MESH: CASP8 and FADD-Like Apoptosis Regulating Protein, MESH : Drug Design, MESH: Mice, Inbred NOD, apoptosis and human diseases, MESH : Multiple Sclerosis, Clinical Biochemistry, CASP8 and FADD-Like Apoptosis Regulating Protein, Arthritis, MESH : Alzheimer Disease, Apoptosis, MESH : Alternative Splicing, Disease, MESH : Models, Biological, MESH: Drug Design, Arthritis, Rheumatoid, MESH : Diabetes Mellitus, Type 1, Mice, 0302 clinical medicine, MESH: Lymphoproliferative Disorders, Mice, Inbred NOD, Neoplasms, MESH: Autoimmune Diseases, Drug Discovery, MESH: Neoplasms, MESH: Animals, MESH : Cardiovascular Diseases, 0303 health sciences, MESH: Arthritis, Rheumatoid, MESH : Gene Expression Regulation, MESH : Lymphoproliferative Disorders, MESH: Alternative Splicing, Intracellular Signaling Peptides and Proteins, MESH: Gene Expression Regulation, 3. Good health, Neoplasm Proteins, medicine.anatomical_structure, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Molecular Medicine, Signal transduction, Alzheimer's disease, MESH: Diabetes Mellitus, Type 1, Signal Transduction, Multiple Sclerosis, c-FLIP, T cell, Biology, Inhibitor of apoptosis, Models, Biological, Article, Autoimmune Diseases, 03 medical and health sciences, MESH : Neoplasm Proteins, MESH : Autoimmune Diseases, MESH : Intracellular Signaling Peptides and Proteins, Alzheimer Disease, MESH: Intracellular Signaling Peptides and Proteins, MESH : Mice, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Pharmacology, MESH : Signal Transduction, MESH: Humans, MESH : Mice, Inbred NOD, MESH: Apoptosis, MESH : Humans, MESH: Models, Biological, MESH: Cardiovascular Diseases, MESH: Multiple Sclerosis, MESH : CASP8 and FADD-Like Apoptosis Regulating Protein, medicine.disease, MESH : Neoplasms, Lymphoproliferative Disorders, Alternative Splicing, Diabetes Mellitus, Type 1, Gene Expression Regulation, Flip, Drug Design, Immunology, MESH : Arthritis, Rheumatoid, MESH : Animals, MESH: Alzheimer Disease, MESH : Apoptosis
Abstract

International audience; Cellular FLIP (c-FLIP), also known as FLICE-inhibitory protein, has been identified as an inhibitor of apoptosis triggered by engagement of death receptors (DRs) such as Fas or TRAIL (TNF-related apoptosis-inducing ligand). cFLIP is recruited to DR signalling complexes, where it prevents caspase activation. Animal models have indicated that c-FLIP plays an important role in T cell proliferation and heart development. Abnormal c-FLIP expression has been identified in various diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), diabetes mellitus, rheumatoid arthritis (RA) and various cancers. This review focuses on recent insights into c-FLIP dysregulation associated with human diseases and addresses the possibilities of using c-FLIP as a therapeutic target.

Published
2003
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16. Caffeine Sensitizes Human H358 Cell Line to p53-mediated Apoptosis by Inducing Mitochondrial Translocation and Conformational Change of BAX Protein

Author

Laurence Dubrez, Jean-Luc Coll, Eric Solary, Amandine Hurbin, Marie-Christine Favrot, Groupe de Recherche sur le Cancer du Poumon, Université Joseph Fourier - Grenoble 1 (UJF), Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hurbin, Amandine

Subjects
p53, Protein Conformation, [SDV]Life Sciences [q-bio], Cell, Mitochondrion, NSCLC, Biochemistry, 0302 clinical medicine, Cytosol, BAX conformation, Tumor Cells, Cultured, Etoposide, bcl-2-Associated X Protein, caffeine, 0303 health sciences, biology, Cell Death, apoptosis, Transfection, Cell biology, Mitochondria, [SDV] Life Sciences [q-bio], Protein Transport, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Vincristine, 030220 oncology & carcinogenesis, Plasmids, Programmed cell death, Blotting, Western, Antineoplastic Agents, Cell Line, 03 medical and health sciences, Bcl-2-associated X protein, Proto-Oncogene Proteins, medicine, Humans, Molecular Biology, 030304 developmental biology, Nucleic Acid Synthesis Inhibitors, Dose-Response Relationship, Drug, BAX translocation, Cell Biology, Genes, p53, Molecular biology, Antineoplastic Agents, Phytogenic, Apoptosis, Cell culture, Xanthines, biology.protein, Central Nervous System Stimulants, Cisplatin, Tumor Suppressor Protein p53
Abstract

International audience; The mechanisms involved in p53-mediated cell death remain controversial. In the present study, we investigated this cell death pathway by stably transfecting the p53-null H358 cell line with a tetracycline-dependent wild type p53-expressing vector. Restoration of p53 triggered a G 2 /M cell cycle arrest and enhanced BAX protein expression, without inducing apoptosis or potentiating the cytotoxic effect of etoposide, vincristine, and cis-platinum. Accordingly, overexpression of BAX in H358 cells, through stable transfection of a tetracycline-regulated expression vector, did not induce cell death. Interestingly, the methylxanthine caffeine (4 mM) promoted the translocation of BAX from the cytosol to the mitochondria. In the setting of an overexpression of BAX, caffeine induced a conformational change of the protein and apoptosis. The consequences of caffeine were independent of its cell cycle-related activities. All together, caffeine synergizes with p53 for inducing cell death through a cell cycle-independent mechanism, involving mitochondrial translocation and conforma-tional change of BAX protein.

Published
2001
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17. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines

Author

Julien, Taieb, Nathalie, Chaput, Noël, Schartz, Stéphan, Roux, Sophie, Novault, Cédric, Ménard, François, Ghiringhelli, Magali, Terme, Antoine F, Carpentier, Guillaume, Darrasse-Jèze, Guillaume, Darrasse-Jèse, François, Lemonnier, Laurence, Zitvogel, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Biologie et thérapeutique des pathologies immunitaires (BTPI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Immunité Cellulaire Antivirale, Institut Pasteur [Paris], This work is supported by a Poste d’accueil Institut National de la Santé et de la Recherche Médicale and Assistance Publique Hopitaux de Paris (to J.T.) and is supported by a European fellowship in the QLRT-2001-00093 and by Association de Recherche contre le Cancer (to N.C.). This work has also been supported by the EC ALLOSTEM grant, by DC THERA European grant, by the Association de Recherche contre le Cancer, and by the LIGUE LABELLISEE française contre le Cancer cancéropôle, Ile de France., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Novault, Sophie

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Melanoma, Experimental, MESH: Vaccines, Subunit, MESH: Adjuvants, Immunologic, CD8-Positive T-Lymphocytes, Pharmacology, MESH: Antineoplastic Agents, Alkylating, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, MESH: Mice, Knockout, MESH: Cancer Vaccines, Mice, 0302 clinical medicine, MESH: Cytoplasmic Vesicles, polycyclic compounds, Immunology and Allergy, MESH: Animals, IL-2 receptor, Cells, Cultured, Mice, Knockout, Mice, Inbred BALB C, MESH: Dendritic Cells, FOXP3, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Killer Cells, Natural, [SDV] Life Sciences [q-bio], MESH: Melanoma, Experimental, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Vaccines, Subunit, MESH: Immunotherapy, Adoptive, Female, hormones, hormone substitutes, and hormone antagonists, MESH: Cells, Cultured, MESH: Killer Cells, Natural, MESH: Mice, Transgenic, T cell, Immunology, MESH: Mice, Inbred BALB C, Mice, Transgenic, Biology, Major histocompatibility complex, Cancer Vaccines, Exosome, 03 medical and health sciences, Adjuvants, Immunologic, medicine, Animals, Humans, Antineoplastic Agents, Alkylating, Cyclophosphamide, MESH: Mice, MESH: Humans, MESH: T-Lymphocytes, Regulatory, Cytoplasmic Vesicles, MESH: Cyclophosphamide, Dendritic Cells, Immunotherapy, Microvesicles, CTL, biology.protein, MESH: Female, 030215 immunology
Abstract

Dendritic cell-derived exosomes (DEX) are nanomeric vesicles harboring MHC/peptide complexes capable of promoting primary T cell responses and tumor rejection in the presence of adjuvants. In this study, we show that, in the absence of adjuvants, DEX mediate potent Ag-dependent antitumor effects against preestablished tumors in mice pretreated with immunopotentiating dosing of cyclophosphamide. Cyclophosphamide could 1) abolish the suppressive function of CD4+CD25+Foxp3+ regulatory T cells, 2) markedly enhance the magnitude of secondary but not primary CTL responses induced by DEX vaccines, 3) synergize with DEX in therapy but not prophylaxis tumor models. Therefore, therapeutic vaccines such as DEX aimed at boosting tumor-primed effector T cells could benefit procedures that minimize the effects of CD4+CD25+ regulatory T cells.

Published
2006
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18. Phenobarbital induction of aldehyde dehydrogenase type 2 mRNA in mouse liver: A candidate region on chromosome 7 for a putative regulatory gene

Author

Marc, N., Alain FAUTREL, Damon, M., Guillouzo, A., Corcos, L., Détoxication et réparation Tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité mixte de recherche veau et porc (UMR VP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Supérieure Agronomique de Rennes, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], [INFO]Computer Science [cs], GENETIQUE
Abstract

International audience; Phenobarbital (PB) strongly induces in the liver the expression of many genes encoding detoxication enzymes, such as the aldehyde dehydrogenase type 2 in the mouse (Aldh2). With the aim of identifying genes involved in this response, we have undertaken an approach based on a genetic analysis in mice. In a previous report, the genetic analysis of both the C57BL/6J (B6) × DBA/2J (D2) F1 and the (F1 × F1) F2 led us to the hypothesis that Aldh2 responsiveness to PB was under the control of one major locus independent of the structural gene. In the present study, the genetic analysis of the inducibility by PB of Aldh2 in the backcross population B6D2F1 × D2 has allowed us to confirm the involvement of a major regulatory gene in this mechanism. By searching for genetic linkage between this locus and a series of microsatellites DNA markers, we obtained indicative evidence for a region on chromosome 7, which may carry this gene.

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19. [To stimulate or to inhibit nitric oxide production in mammary tumors?].

Author

Gauthier N, Arnould L, Chantôme A, Reisser D, Bettaieb A, Reveneau S, and Jeannin JF

Subjects
Animals, Apoptosis, Breast Neoplasms blood supply, Breast Neoplasms pathology, Capillary Permeability, Humans, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental therapy, Neoplasm Invasiveness, Neovascularization, Pathologic etiology, Nitric Oxide antagonists & inhibitors, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Breast Neoplasms metabolism, Nitric Oxide metabolism
Abstract

NO is a molecule produced in different amounts by two types of enzymes, constitutive NO-synthases and inducible NO-synthase, the last one produce large amount of NO. In tumor outcome, its role may be either beneficial or detrimental due to its actions in the different steps of tumor growth and metastasis. This review deals with mammary tumors and the mechanisms lying behind NO effects. In human patients, increased amounts of NO were evidenced in blood, linked with the presence and activity of NO-synthase in breast tumors. Non-unequivocal correlations were established with tumor grade, invasiveness and metastatic potential. Studies in animal models have given hints to explain these discrepancies by the type of the involved NO-synthase, the amount of NO it produces, and its belonging to tumoral or stromal cells. Indeed, it was recently shown that NO produced by tumor cells inhibits, while NO produced by stromal cells facilitates tumor growth, at least in the model which was studied. On the one hand, NO toxicity against tumor cells is a well known phenomenon, but on the other hand, NO may promote tumor invasiveness due to its effect on extracellular matrix, and to its angiogenetic properties. So the role of NO in mammary tumor outcome is not clear-cut, and, at the present time, it cannot be ascribed a pronostic value in breast tumor. However, researches aimed at managing tumor cells to produce NO sufficient to induce their death may be fruitful since, be tumor targeting successful, no general toxicity would be encountered.

Published
2004

20. [Apoptosis: molecular mechanisms].

Author

Solary E

Subjects
Animals, Apoptosis genetics, Embryonic and Fetal Development, Humans, Mitochondria metabolism, Models, Biological, Morphogenesis, Apoptosis physiology
Abstract

Apoptosis is a genetically programmed cell death that is required for morphogenesis during embryogenic development and for tissue homeostasis in adult organisms. In most cases, apoptosis involves cytochrome c release from mitochondria. In the cytosol, cytochrome c combines with APAF-1 in the presence of ATP to activate caspase-9 that, in turn, activates effectors caspases such as caspase-3. Bcl-2 and related proteins control cytochrome c release from the mitochondria whereas IAP (for Inhibitor of APoptosis) molecules modulate the activity of caspases. Plasma membrane receptors such as Fas (CD95, APO-1), characterized by a so-called "death domain" in their cytoplasmic domain, can activate the caspase cascade through adaptator molecules such as FADD (Fas-Associated protein with a Death Domain). Dysregulation of the apoptotic machinery plays a role in the pathogenesis of various diseases and molecules involved in cell death pathways are potential therapeutic targets in immunologic, neurologic, cancer, infectious and inflammatory diseases.

Published
1998

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