Cellular Metabolism Regulates Anti-Oxidant Response Through ERK5-MEF2 Pathway Abrar Ul Haq Khan To cite this version: Abrar Ul Haq Khan. Cellular Metabolism Regulates Anti-Oxidant Response Through ERK5- MEF2 Pathway. Human health and pathology. Université Montpellier, 2017. English. NNT : 2017MONTT036. tel-01684254 HAL Id: tel-01684254 https://tel.archives-ouvertes.fr/tel-01684254 Submitted on 15 Jan 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Délivré par UNIVERSITE DE MONTPELLIER Préparée au sein de l’école doctorale CBS2 n°168 - Sciences Chimiques et Biologiques pour la Santé Et de l’unité de recherche INSERM U1183 - Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.) Spécialité: Biologie Santé Présentée par KHAN Abrar Ul Haq Cellular Metabolism Regulates Anti-Oxidant Response Through ERK5-MEF2 Pathway Rôle de la voie ERK5-MEF2 dans la régulation de la réponse anti-oxydante par le métabolisme cellulaire Soutenue le 27 /06/2017 devant le jury composé de Mme Naomi TAYLOR , DR Président du Jury IGMM, Montpellier Mr Rodrigue ROSSIGNOL , DR Rapporteur MRGM, Bordeaux Mme Sophie VASSEUR , DR Rapporteur CRCM, Marseille Mme Nathalie ANDRIEU , DR Examinateur CRCT, Toulouse Mr Guillaume BOSSIS , CR Examinateur IGMM, Montpellier Mr Martin VILLALBA , DR, Directeur de thèse I.R.M.B. Montpellier ! ACKNOWLEDGMENT First and foremost I am obliged to the almighty ALLAH, for showering HIS blessings and enabling me for this honor. Without any doubt I would like to present my amplest gratefulness to Dr. Martin Villalba for his kind supervision and scientific guidance throughout my PhD research. His supportive attitude always gave me extraordinary confidence during theses nerve testing process. I always found unflinching encouragement and support from him. I will not hesitated to mention that his pleasant scientist’s intuition built in me a constant oasis of ideas and cravings of science, which exceptionally inspire and enrich my growth as a student, a researcher and a scientist. I am beholden to him beyond his consideration. I simply cannot wish for a better and friendlier supervisor. Martin you never behaved with a bossy attitude and your office door was always open for me and I never felt hesitant to discuss any issue I faced regarding science or in person, bundle of thanks for fullest support. I deem it paramount pleasure to avail this occasion to express the sincerest gratitude and a deep sense of obligation to Martin for his nimble leadership, analytical arbitration, compassionate insolence and inspirational determinations to indoctrinate in me the spirit of scientific motivation and developed writing dexterities during the course of my research work. I perhaps do not have superior words to definite my inner sensation and appreciativeness towards you. I am obliged to the “Higher Education Commission (HEC)” of Pakistan, its officers and officials for funding my doctorates study in France within their limited resources. I am also thankful to CHU Montpellier for funding my last year of thesis. I must also mention the services provided by Campus France to facilitate my living in France. I zealously extend my profound thanks to the participants of my thesis jury Mme Naomi Taylor, Mr. Rodrigue Rossignol, Mme Sophie Vasseur, Mme Nathalie Andrieu, Mr. Guillaume Bossis and once again to my thesis director. I would also not forget to reflect my gratitude to Delphine Gitenay, Nerea Allende- Vega, Dang-Nghiem Vo, Sana Belkahla, Catherine Alexia, Cecile Saout, Javier Hernandez, Amelie Carnillon and former lab members Moeez Ghani, Ewelina ! krzywinska, Nuria Lopez, Diego Sanchez, Ludovic Gabellier, Gabriel Espinosa and Johan Garaude for their teamwork and livelihood in every aspect. I will especially thanks to Sabine Gerbal, Claire Gondeau, Martine Daujat and Charles Lecillier for their support in my work regarding lipid metabolism and miRNA. I am also indebted to my all colleagues and administration of Institute for Regenerative Medicine and Biotherapy (IRMB) U1183 INSERM and I would like to imitate my gratitude especially to Prof. Christian Jorgensen who is leading the institute from the front. Finally, I will always be indebted to my family particularly to my mother for her countless prayers. My unpretentious recognitions are to all my family members who were always there for my support throughout my study. I will dedicate this thesis in honor to my late father (RIP). ! Table of Contents Abbreviations ........................................................................................................................ 1 Abstract ................................................................................................................................. 3 Résumé .................................................................................................................................. 5 1. Metabolism ............................................................................................................ 8 1.1. Cellular Respiration .................................................................................................. 9 1.1.1. Glucose Metabolism ............................................................................................. 9 1.1.2. Fructose Metabolism .......................................................................................... 11 1.1.3. Galactose Metabolism ........................................................................................ 12 1.1.4. The Krebs cycle (Citric acid cycle or Tricarboxylic acid cycle) ........................ 13 1.1.5. Oxidative phosphorylation (OXPHOS) .............................................................. 14 1.2. Lactic acid Fermentation ........................................................................................ 17 1.3. Glutaminolysis .......................................................................................................... 17 1.3.1. Glutamine metabolism and cancer ...................................................................... 18 1.4. Lipid metabolism ..................................................................................................... 20 1.4.1. Lipid metabolism and cancer .............................................................................. 21 1.5. Tumor metabolism ................................................................................................... 22 2. Dichloroacetate .................................................................................................... 29 2.1. Dichloroacetate in Cancer ....................................................................................... 31 2.2. DCA and Lipids homeostasis .................................................................................. 37 3. Cellular Signaling ............................................................................................... 41 3.1. MAPK Extra Regulated Kinase 5 (ERK5) ............................................................ 43 3.1.1. Structure of ERK5 .............................................................................................. 43 3.1.2. Activation of ERK5 ............................................................................................ 44 3.2. Biological Roles of ERK5 ........................................................................................ 46 3.3. ERK5 in Cancer ....................................................................................................... 47 3.3.1. Oncogenes and ERK5 ......................................................................................... 47 3.3.2. ERK5 and Tumorigenesis ................................................................................... 48 3.3.3. ERK5 and leukemia ............................................................................................ 48 3.3.4. ERK5 and Tumor progression ............................................................................ 49 3.3.5. ERK5 and tumor metastasis ................................................................................ 50 3.3.6. ERK5 and tumor resistance to cell death ............................................................ 50 3.3.7. ERK5 and Tumor associated angiogenesis ......................................................... 52 3.4. ERK5 and Tumor suppressive miRNAs ................................................................ 52 3.5. Inhibitors of MEK5/ERK5 ...................................................................................... 53 4. Cellular Redox Homeostasis .............................................................................. 57 4.1. NFE2L2 (NRF2) ....................................................................................................... 57 4.2. KEAP1 ...................................................................................................................... 58 4.3. Regulation of NRF2/KEAP1 Pathway ................................................................... 59 4.4. NRF2 Response mechanism ...................................................................................