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Hélène LALLET-DAHER Implication Du Canal Potassique Calcium

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Hélène LALLET-DAHER Implication Du Canal Potassique Calcium Université des Sciences et Technologies de Lille Année 2008 N° d’ordre : 4313 THESE Présentée pour l’obtention du grade de : DOCTEUR DE L’UNIVERSITE DES SCIENCES ET TECHNOLOGIES DE LILLE Discipline : Biologie-Santé Par Hélène LALLET-DAHER Implication du canal potassique calcium dépendant à conductance intermédiaire IK Ca1 dans la cancerogenèse de la prostate humaine. Thèse dirigée par le Professeur Morad ROUDBARAKI Soutenue le Mardi 16 Décembre 2008 Jury : Dr. Joël MAZURIER, CNRS, Université de Lille 1 Président Pr. Halima OUADID AHIDOUCH, Université de Picardie Jules-Verne, Amiens Rapporteur MCF Christophe VANDIER, Université de Tours Rapporteur MCF Olivier SORIANI, Université de Nice Sophia-Antipolis Examinateur Pr. Morad. ROUDBARAKI, Université de Lille 1 Examinateur Pr. Natalia PREVARSKAYA , Université de Lille 1 Examinateur RESUME Implication du canal potassique calcium-dépendant IK Ca1 dans la cancérogenèse de la prostate humaine Des études récentes montrent que l’homéostasie calcique intracellulaire, ainsi que l’expression et l’activité de canaux ioniques jouent un rôle essentiel dans le contrôle de la prolifération cellulaire aussi bien dans un contexte physiologique que dans certains cancers. Cependant, aucune approche proposant les canaux ioniques comme cible thérapeutique n'est actuellement envisagée dans le cadre des traitements des cancers de la prostate. Dans ce travail nous avons mis en évidence l’expression, la fonctionnalité et l’implication des canaux potassiques calcium-activés (IK Ca1 ) dans la prolifération des lignées cellulaires cancéreuses de la prostate humaine. Ces études ont également montré que l’activation du canal IK Ca1 favorise l’entrée de calcium via un canal calcique de la famille des TRP, le canal TRPV6, impliqué dans l’entrée passive de calcium dans les cellules cancéreuses prostatiques. De plus, par des études de co- immunoprécipitations, nous avons montré que le canal IK Ca1 et le canal calcique TRPV6 sont associés formant ainsi un complexe moléculaire fonctionnel permettant l’entrée de calcium et la prolifération des cellules cancéreuses prostatiques humaines. Par ailleurs, une suppression du canal IK Ca1 induit la différenciation neuroendocrine des cellules cancéreuses prostatiques humaines. Ceci suggère un rôle essentiel joué par le canal IK Ca1 pour favoriser la croissance ou induire la différenciation cellulaire. Nos études ont également mis en évidence une surexpression de l’ARNm et de la protéine d’ IK Ca1 dans les tissus prostatiques atteints d’un cancer de la prostate humaine. Ces données permettraient de proposer ces canaux ioniques comme marqueurs de cancer et/ou comme cibles thérapeutiques potentielles dans le traitement des cancers de la prostate humaine. SUMMARY Implication of calcium-activated potassium channel IK Ca1 in human prostate cancer Recent studies show that the intracellular calcium homeostasis, as well as expression and the activity of ionic channels play an essential role in the control of cell proliferation as well in a physiological context as in certain cancers. However, no approaches offering ionic channels as therapeutic target is nowadays envisaged as part of the treatments of the cancers of the prostate. In the present work, we showed the expression, functionality and involvement of calcium- activated potassium channels (IK Ca1 ) in the proliferation of the human prostate cancer cells. These studies also showed that the activation of the IK Ca1 channel favours the calcium entry via a member of the TRP family of calcium channels, TRPV6, in the prostate cancer cells. Besides, by studies of co-immunoprécipitations, we showed that the IK Ca1 potassium channel and the TRPV6 calcium channel form a functional molecular complex allowing the calcium entry and the proliferation of the prostate cancer cells. Moreover, a down-regulation of the IK Ca1 channel leads to the neuroendocrine differentiation of the human prostate cancer cells. This suggests an essential role played by the IK Ca1 channel to favour growth or lead to cell differentiation. Our immunohistofluorescence studies also showed an overexpression of IK Ca1 mRNA and protein in human prostate cancer compared to non-tumor tissues. These data would allow to propose these ion channels as markers and/or as potential therapeutic targets in the treatment of the human prostate cancers. A Wassim, A mes parents, A ma famille Je tiens à exprimer toute ma gratitude aux membres du jury : Mesdames, Messieurs les membres du jury veuillez accepter mes sincères remerciements pour avoir accepté de juger cette thèse. Ayant bien conscience du temps nécessaire que vous avez consacré à la lecture et à l’analyse critique de ce travail, j’espère, humblement, avoir participer à l’enrichissement de vos connaissances sur les canaux potassiques et leur implication dans la physiopathologie de la prostate. Monsieur le Président , c’est pour moi un grand honneur que vous ayez accepté de présider ce jury. Veuillez accepter mes sincères remerciements. Madame le Pr. H. Ouadid Aidouch et Monsieur le Dr. C. Vandier , veuillez recevoir toute ma gratitude pour votre lecture critique de ce manuscrit de thèse, pour laquelle vous avez accepté de consacrer votre temps. Soyez assuré de mes profonds remerciements. Monsieur le Dr. O. Soriani , je vous suis très reconnaissante d’avoir accepté de juger ce travail et d’en être l’examinateur. Veuillez accepter mes plus sincères remerciements pour votre présence dans ce jury. Madame le Pr. N. Prevarskaya , je vous remercie de m’avoir accueilli dans votre laboratoire et de m’avoir fait confiance tout au long de ces quatre années de thèse. Monsieur le Pr. M. Roudbaraki , je tiens à vous exprimer toute ma reconnaissance pour ces quatre années de thèse. Remerciements généraux : Comme le veut la tradition, je vais tenter de satisfaire au difficile exercice de la page des remerciements de façon générale, peut-être la tâche la plus ardue de ces années de thèse ! Non qu'exprimer ma gratitude envers les personnes en qui j'ai trouvé un soutien soit contre ma nature, bien au contraire. La difficulté tient plutôt dans le fait de n'oublier personne. C'est pourquoi, je remercie par avance ceux dont le nom n'apparaît pas dans cette page et qui m'ont aidé d'une manière ou d'une autre. Qu’ils trouvent ici le témoignage de ma reconnaissance et plus particulièrement les membres de l’unité INSERM U800. « Faire une thèse» est une échappée solitaire aux milieux de compagnons de fortune (ou d'infortune). On ne se rend pas toujours compte à quel point ils peuvent être importants dans le travail et dans la vie, jusqu'au jour où nos chemins se séparent. Je tiens à remercier Agathe pour son amitié, sa présence dans les bons et les mauvais moments, pour toutes ces formidables discussions sur tous les sujets possibles et inimaginables que je ne peux partager qu’avec elle. Mais surtout un grand merci pour m’avoir supporter pendant mes moments « Hulkiens » comme tu les nommes si bien. Cette thèse aura eu le mérite d’être à la base de notre amitié . Loïc , un grand merci pour tes conseils, pour les discussions passionnantes que nous avons eues et j’espère qu’il y en aura bien d’autre. Je tiens également à remercier les « garçons » ( Matthieu et Olivier bien sûr) pour leurs bonnes humeurs de tous les jours. Toute mon amitié à Chantal avec qui j'ai partagé les joies et les peines de cette thèse. Merci aussi à tous mes collègues du laboratoire qui se reconnaîtront ici. Je leur exprime ma profonde sympathie. A mes parents et à ma grand-mére, je tiens à vous remercier tout particulièrement pour m’avoir toujours soutenu dans mes choix, d’avoir été à mes cotés. Merci pour vos encouragements, votre présence et pour tout l’Amour dont vous m’avez entouré depuis le début. Merci également à ma belle-famille pour leurs soutiens. Wassim , comme on dit, le meilleur pour la fin. Je n’aurai pas assez de l’intégralité de ce manuscrit pour te dire tout ce que je veux. Tout simplement MERCI. GLOSSAIRE 5 INTRODUCTION 9 I- Physiopathologie de la prostate humaine 10 A- La glande prostatique 10 1- Anatomie 10 2- Histologie 12 2.1- Le stroma 12 2.2- Le tissu glandulaire 12 B- Rôles physiologiques de la glande prostatique 17 1- Rôle sécrétoire de la prostate 17 2- Rôle mécanique de la prostate 18 C- Les pathologies prostatiques 18 1- La prostatite 19 2- Adénome ou Hyperplasie Bénigne de la Prostate (HBP) 19 3- Le cancer de la prostate 19 3.1- Histoire naturelle du cancer 20 3.2- Evolution du cancer de la prostate 20 3.3- Hormones et cancer 21 a- Rôle des hormones mâles 21 b- De l’hormono-dépendance à l’hormono-résistance 21 c- Echappement hormonal : mécanismes cellulaires 23 - Apoptose 23 - Perturbation de la prolifération 28 - Différenciation neuroendocrine 29 3.4- Les métastases 30 3.5- Epidémiologie du cancer de la prostate 31 3.6- Facteurs de risque 31 a- Facteurs de risques constitutionnels 31 b- Facteurs de risques environnementaux 32 3.7- La classification oncologique 32 a- Le système TNM 32 b- Le système de gradation de Gleason 34 E- Diagnostics 35 1- Examens cliniques 35 2- Examens biologiques : dosage du taux de PSA 35 3- Prélèvements tissulaires prostatiques 36 F- Les traitements du cancer 37 1- Les traitements curatifs 37 2- Les traitements palliatifs 37 G- L’avenir dans le traitement du cancer de la prostate 39 II- L’homéostasie calcique : implication dans la physiologie et physiopathologie cellulaire 39 A- Prolifération et calcium 41 B- Principales sources de calcium 42 C- Caractéristiques des signaux calciques 44 1- Régulation spatio-temporelle
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