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Elie Dib Hadchity

Associate professor
Chemistry - Biochemistry department - Section I - Hadath
Speciality: Biochemistry
Specific Speciality: Biochimie physique

Positions
Education
2006 - 2006: Diplôme Universitaire

Ecole Normale Supérieure de Lyon-Université Claude Bernard Lyon I
Formation à l’Expérimentation Animale de Niveau I

2004 - 2009: PhD

Claude Bernard University Lyon 1
Biochimie Physique (Radiobiology)

Associate Professor

2003 - 2004: Master 2

Claude Bernard University - Lyon 1
Biochimie

MS

2002 - 2003: Maitrise

Faculty of Sciences - Lebanese University
Biochimie

Conferences 16 participations
FEBS EMBO Conference, Paris, France

Conference
2014-08-30 to 2014-09-04

4eme Journée Scientifique. Faculté des Sciences USEK

Poster session
2014-05-08 to 2014-05-08

3eme Journée Scientifique. Faculté des Sciences USEK

Poster session
2013-04-26 to 2013-04-26

2eme Journée Scientifique. Faculté des Sciences USEK

Poster session
2012-05-16 to 2012-05-16

18th International Science Meeting: New Discoveries in Science, Notre Dame University

Conference
2012-03-22 to 2012-03-24

4th International Conference on Drug Discovery and Therapy, Dubai

Conference
2012-02-12 to 2012-02-15

10ème Colloque International de Radiobiologie Fondamentale et Appliquée, Anglet-France.

Congress
2011-09-11 to 2011-09-16

14th International Congress of Radiation Research, Warsaw, Poland.

Congress
2011-08-28 to 2011-09-01

Journée Scientifique. Faculté des Sciences

Poster session
2011-05-18 to 2011-05-18

9ème Colloque International de Radiobiologie Fondamentale et Appliquée, Annecy-France

Congress
2009-09-20 to 2009-09-25

3ème Journée Scientifique du CLARA, Lyon

Seminar
2008-03-18 to 2008-03-19

8ème Colloque International de Radiobiologie Fondamentale et Appliquée, La Londes Les Maures-France

Congress
2007-09-16 to 2007-09-21

13th International Congress of Radiation Research, San Francisco, California, USA

Congress
2007-07-08 to 2007-07-12

11ème Journée Scientifique de l’EDISS

Poster session
2007-03-29 to 2007-03-29

2ème Journée Scientifique du CLARA, Grenoble

Seminar
2007-03-19 to 2007-03-20

American Association for Cancer Research, Molecular Targets and Cancer Therapeutics, Clinical Cancer Research, Philadelphia, USA

Conference
2005-11-14 to 2005-11-18

Publications 5 publications
B Gibert, E Hadchity, A Czekalla, M-T Aloy, P Colas, C Rodriguez-Lafrasse, A-P Arrigo Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers Macmillan (nature publishing group) 2011

Human heat shock protein 27 (Hsp27, HspB1) is an antiapoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. Hsp27 biochemical properties rely on a structural oligomeric and dynamic organization. Downregulation by small interfering RNA or inhibition with dominant-negative mutant have proven their efficiency to counteract the antiapoptotic and protective properties of Hsp27. In this study, we report the isolation and characterization of Hsp27-targeted molecules interfering with its structural organization. Using the peptide aptamer (PA) strategy, we isolated PAs that specifically interact with Hsp27 and not with the other members of the small heat shock protein family. In mammalian cell cultures, PAs expression perturbed the dimerization and oligomerization of Hsp27, and acted as negative regulators of the antiapoptotic and cytoprotective activities of this protein. Further studies analyzing SQ20B cell xenografts in immunocompromised mice showed that PAs strongly reduced tumor development through cell cycle arrest. Our data suggest that PAs could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors.

Hadchity E, Aloy MT, Paulin C, Armandy E, Watkin E, Rousson R, Gleave M, Chapet O, Rodriguez-Lafrasse C. Heat shock protein 27 as a new therapeutic target for radiation sensitization of head and neck squamous cell carcinoma. Molecular Therapy, The American Society of Gene & Cell Therapy (nature publishing group) 2009

In a wide range of human cancers, increased levels of heat shock protein 27 (Hsp27) are closely associated with tumorigenesis, metastasis, resistance to anticancer therapeutics, and thus poor prognosis. In this study, we evaluate the radiosensitizing effects of Hsp27 gene silencing using OGX-427, a second-generation antisense oligonucleotide (ASO), on the radioresistant head and neck squamous cell carcinoma (HNSCC) SQ20B cells. In vitro, the downregulation of Hsp27 significantly enhanced radiation-induced apoptotic and clonogenic death, and promoted Akt inactivation. In vivo, combining OGX-427 with local tumor irradiation (5 × 2 Gy) led to a significant regression of SQ20B tumors related to a high rate of apoptosis and decreased levels of glutathione antioxidant defenses. Increasing the total radiation dose (15 × 2 Gy) significantly amplified the radiosensitizing effect of OGX-427. Treatment of tumors with OGX- 427 plus radiation resulted in a decrease in angiogenesis associated with a reduced activation of the Akt pathway. Furthermore, the combined treatment enhanced the survival of SQ20B-bearing mice and showed no signs of acute and delayed toxicity. Our findings demonstrate for the first time that Hsp27 knockdown enhances the cytotoxic effects of radiotherapy in vivo and provide preclinical proof of principle for clinical trials using Hsp27 antisense technology in the treatment of patients with HNSCC radioresistant cancers.

RODRIGUEZ-LAFRASSE C and HADCHITY E. International Patent : Treatment of squamous cell carcinoma with Hsp27 antisense oligonucleotides and radiotherapy International Patent PCT/CA2008/000419 (WO 2008/106781) 2009

Squamous cell carcinomas, such as squamous head and neck cancer, are treated with a combination of radio-therapy and a therapeutic agent that reduces the amount of hsp27 in the squamous cancer cells. In specific embodiments, the therapeutic agent that reduces the amount of hsp27 is an antisense oligonucleotide therapeutic agent.

Aloy MT*, Hadchity E*, Bionda C, Diaz-Latoud C, Claude L, Rousson R, Arrigo AP, Rodriguez-Lafrasse C. Protective role of Hsp27 protein against gamma radiation-induced apoptosis and radiosensitization effects of Hsp27 gene silencing in different human tumor cells. Int. J. Radiation Oncology Biol. Phys, ELSEVIER 2008

Purpose: The ability of heat shock protein 27 (Hsp27) to protect cells from stressful stimuli and its increased levels in tumors resistant to anticancer therapeutics suggest that it may represent a target for sensitization to radiotherapy. In this study, we investigate the protective role of Hsp27 against radiation-induced apoptosis and the effect of its attenuation in highly expressing radioresistant cancer cell lines. Methods and Materials:We examined clonogenic death and the kinetics of apoptotic events in different tumor cell lines overexpressing or underexpressing Hsp27 protein irradiated with photons. The radiosensitive Jurkat cell line, which does not express Hsp27 constitutively or in response to g-rays, was stably transfected with Hsp27 complementary DNA. Attenuation of Hsp27 expression was accomplished by antisense or RNAi (interfering RNA) strategies in SQ20B head-and-neck squamous carcinoma, PC3 prostate cancer, and U87 glioblastoma radioresistant cells. Results: We measured concentration-dependent protection against the cytotoxic effects of radiation in Jurkat- Hsp27 cells, which led to a 50% decrease in apoptotic cells at 48 hours in the highest expressing cells. Underlying mechanisms leading to radiation resistance involved a significant increase in glutathione levels associated with detoxification of reactive oxygen species, a delay in mitochondrial collapse, and caspase activation. Conversely, attenuation of Hsp27 in SQ20B cells, characterized by their resistance to apoptosis, sensitizes cells to irradiation. This was emphasized by increased apoptosis, decreased glutathione basal level, and clonogenic cell death. Sensitization to irradiation was confirmed in PC3 and U87 radioresistant cells. Conclusion: Hsp27 gene therapy offers a potential adjuvant to radiation-based therapy of resistant tumors.

Bionda C, Hadchity E, Alphonse G, Chapet O, Rousson R, Rodriguez-Lafrasse C, Ardail D. Radioresistance of human carcinoma cells is correlated to a defect in raft membrane clustering. Free Radical Biology & Medicine, ELSEVIER 2007

In addition to DNA damage, exposure to irradiation involves the plasma membrane in the early phases of gamma-ray-induced cell death. The involvement of raft microdomains following gamma-radiation derives essentially from the role of ceramide as a critical component leading to apoptosis. It is demonstrated here that gamma-irradiation of a radiosensitive human head and neck squamous carcinoma cell line (SCC61) results in the triggering of raft coalescence to larger membrane platforms associated with the externalization of an acid sphingomyelinase (A-SMase), leading to ceramide release in raft, 30 min postirradiation. For the first time, we show that this structural rearrangement is defective in the radioresistant SQ20B cells and associated with the lack of A-SMase activation and translocation, a result which could explain in part their resistance to apoptosis following ionizing radiation. Moreover, we show that SQ20B are protected against radiation injury through a fivefold upper level of endogenous glutathione compared to SCC61. Overcoming the endogenous antioxidant defenses of SQ20B through either H(2)O(2) treatment or GSH depletion triggers A-SMase activation and translocation, raft coalescence, and apoptosis. On the contrary, ROS scavengers abolished these events in radiosensitive SCC61 cells. Translation of this concept to tumor biology suggests that manipulation of rafts through redox equilibrium may provide opportunities for radiosensitization of tumor cells.

Supervision 3 Supervised Students
Study of nucleophosmin NPM protein in the response of endothelial cells to the oxidative stress induced by radiation

Hala Elias Estephan
Master M2 Thesis: Oncology in 2015

Etude de la protéine nucléophosmine NPM dans la réponse des cellules endothéliales au stress oxydant radio-induit

Hala Estephan
Stage de Master 2 en Cancérologie en collaboration avec l’équipe 14 "Radiobiologie et Ciblage de l'Endothélium" du Centre de Recherche en Cancérologie Nantes-Angers, France

Dans un contexte thérapeutique de radiothérapie, l’exposition aux rayonnements ionisants a pour but essentiel de détruire la masse tumorale, mais est aussi à l’origine de nombreuses dysfonctions tissulaires, impliquant notamment le compartiment endothélial. L’équipe 14 "Radiobiologie et Ciblage de l'Endothélium" du Centre de Recherche en Cancérologie Nantes-Angers travaille à caractériser sur un plan moléculaire mais aussi fonctionnel la réponse aux radiations initiée à la membrane plasmique des cellules endothéliales. Ses travaux ont ainsi caractérisé l’activation de la voie des protéines p38 MAPK via la génération membranaire du sphingolipide céramide dans l’apoptose endothéliale radio-induite. Par une approche protéomique, l’équipe a très récemment identifié un nouveau partenaire atypique de p38 MAPK dans la réponse endothéliale au stress oxydant, la ribonucléoprotéine nucléophosmine (NPM), protéine multifonctionnelle principalement caractérisée pour son rôle dans la biogénèse des ribosomes. Ce projet de stage proposé a pour objectif de mieux comprendre les mécanismes d’activation de NPM ainsi que le rôle de cette protéine dans les dysfonctions endothéliales induites par le stress oxydant généré par les rayonnements ionisants. Ce projet implique des approches de biologie cellulaire, de biochimie intracellulaire de signalisation et de tests cellulaires in vitro des fonctions endothéliales.

Elucidation du rôle de Klf4 dans le cancer

Alaa Akl
Stage de recherche Master 2

Le cancer reste à nos jours un problème majeur de santé publique et une cause majeure de décès dans le monde. Différentes stratégies thérapeutiques ont été développées et sont actuellement en cours d’application clinique. La compréhension des mécanismes moléculaires de résistance tumorale aux traitements représente une voie de recherche importante pour le développement de nouvelles stratégies thérapeutiques ciblant l’inhibition de tout système impliqué dans la résistance tumorale, permettant ainsi d’améliorer l’efficacité des traitements anticancéreux et la survie des patients. Les facteurs de transcription de type Krüppel (KLF), surexprimés dans de nombreux cancers, pourraient représenter une cible thérapeutique pertinente. Ces facteurs sont impliqués dans la carcinogénèse en agissant comme promoteurs tumoraux en fonction du type et du contexte cellulaires. La surexpression de KLF4, membre de la famille KLF, est reliée à la progression et l'agressivité tumorale et au pouvoir métastasique. L'objectif de ce travail est d’évaluer l’expression de Klf4 dans des lignées tumorales et de corréler son expression à la résistance tumorale. Il s’agit plus précisément de démontrer le rôle anti-apoptotique de cette protéine en réponse à la chimiothérapie. Une fois ce rôle est validé dans nos lignées tumorales, nous procèderons à l’inhibition de son action anti-apoptotique. Cette protéine pourrait être identifiée comme nouvelle cible thérapeutique potentielle.