La plupart des techniques sont décrites dans l’article et cette partie ne décrit que les techniques supplémentaires qui n’y sont pas détaillées.
• Transfection plasmidique
1µg d’ADN des plasmides pIRESPuro2 (Clontech) codant pour RhoBwt-HA ou RhoBQ63L-HA sont transfectés avec de l’Effectène selon les recommandations du fabricant (Qiagen). Après 4h d’incubation, le milieu de transfection est remplacé par du DMEM 10% SVF.
• Immunoprecipitation de PP2A
Les cellules sont lysées dans du tampon RIPA modifié (Tris HCl 50 mM, pH 7.5, NaCl 150 mM, Triton X100 1% et EDTA 5 mM) additionné d’un cocktail d’inhibiteurs de protéases 1% (Biorad) et d’un cocktail d’inhibiteurs de phosphatases 1% (Pierce). 100 µg de protéines sont utilisés pour analyser l’extrait total par immuno-empreinte. Pour l’immuno-précipitation, 800 µg de protéines sont incubés avec 1 µg d’anticorps dirigé contre la sous unité catalytique de PP2A (Millipore) et 25 µL de billes d’agarose A/G (Santa Cruz). Le mélange est incubé à 4°C sous agitation pendant une nuit. Après lavage, les billes sont reprises dans 30 µL de tampon de dénaturation 2.5X (Tris 30 mM, pH 6.8, SDS 50 mM, glycérol 4%, bleu de bromophénol 0.0005%) additionné de DTT 100 mM.
• Test activité PI3K
Le protocole fourni avec le kit de dosage de l’activité PI3K « Activity ELISA : Pico » (Echelon) a été suivit. Brièvement, les cellules sont lysées avec le tampon de réaction kinase 1X fourni complémenté avec de l’ATP 25 µM et du DTT 5 mM. Après immuno-précipitation de la p85, le test d’activité est réalisé.
• Culture cellulaire
Les cellules BEAS-2B (ATCC CRL-9609) sont cultivées dans du DMEM 10% SVF (Sérum de Vœu Fœtal). Les cellules Calu1 (ATCC HTB-54), cellules de carcinome épidermoïde de grade III sont cultivées dans du Mc Coy’s 5a (Gibco) avec 1.5 mM de glutamine et 10% de SVF. Les cellules H1703 (ATCC CRL-5889), H520 (ATCC HTP-182), toutes 2 issues de carcinome épidermoïde et les cellules H2935 (ATCC CRL-5908), H23 (CRL-5800), H1975 (ATCC CRL-5908), H4006 (ATCC CRL-2871), H827 (ATCC CRL-2868), toutes isssues d’adénocarcinomes, sont cultivées dans du milieu Roswell Park Memorial Institute’s (RPMI-1640) (Lonza) complémenté avec 10% SVF.
• Morphologie cellulaire en matrice tri-dimensionnelle
Les cellules contrôles, transfectées ou traitées pendant 1 h avec les inhibiteurs sont reprises dans du collagène I (BD bioscience) dilué à 1.6 mg.mL-1 dans du EMEM (Eagle’s Minimal Essential Medium 2X (lonza) à une concentration de 4.104 cellules.mL-1, les inhibiteurs sont maintenus dans la suspension. Des gouttes de 30 µL sont déposées sur des boites de cultures qui sont ensuite mises à l’envers pendant 1 h. Les boites sont ensuite remises à l’endroit et du milieu de culture complet est ajouté, les inhibiteurs sont également maintenus dans le milieu de culture. 6 h après, les cellules sont rincées au PBS et fixées avec du formaldéhyde 3.7%, perméabilisées au Triton X100 1% et l’actine est marquée avec de la phalloïdine-Alexa594 (Belletti et al., 2010). Les cellules sont ensuite observées au microscope bi-photonique 7MP de Zeiss à l’objectif 20X (Plateforme TRI d’imagerie cellulaire, IFR150, Purpan). 100 cellules sont comptées par goutte et la moyenne est réalisée sur 3 gouttes. La taille des prolongements cellulaires est mesurée avec le logiciel NIS-elementAR de Nikon.
• Zymographie
Les cellules sont privées de sérum pendant 24 h puis le surnageant de culture est récupéré. 60 µL de surnageant additionné de bleu de dépôt sont déposés sur un gel SDS- PAGE 10% d’acrylamide contenant 0.3% de gélatine. Après electrophhorèse des protéines, le gel est rincé dans du tampon (Tris 50 mM, pH7.4, Triton X100 20%) puis dans du tampon Tris 50 mM pH7.4. Il est ensuite incubé sur la nuit à 37°C dans le tampon Tris 50 mM, pH7.4, NaCl2 0.2 M, Triton X100 1%, CaCl2 5 mM et azide de sodium 0.02%. La coloration des
protéines se fait en incubant le gel dans du bleu de Coomassie 0.5% (Bleu 0.5%, méthanol 50%, acide acétique 10%) pendant 24 h.
• Analyse des intégrines par cytométrie de flux
Les cellules sont décollées avec du PBS-EDTA (4 mM) et récupérées dans du DMEM additionné de 10% SVF. Elles sont resuspendues à une concentration de 106 cellules.mL-1 dans du tampon FACS (PBS, BSA 0.5%, SVF 4%) les cellules sont reprises dans du tampon de saturation (PBS, BSA 2%, SVF 1%) à une concentration de 240 000 dans 50 µL. Elles sont ensuite incubées avec la solution d’anticorps primaire dilué au 1/200ème dans le tampon FACS puis dans la solution d’anticorps secondaire couplé au FITC. Les cellules sont ensuite fixées dans du formaldéhyde 3.7% et reprises dans 500 µL de PBS. L’expression des intégrines à la surface des cellules est analysée par cytométrie de flux (FACSCalibur, Becton-Dickinson). L’unité utilisée pour interpréter les résultats est l’Indice de Fluorescence (ISF)
ISF = [(Val. Moy. Exp.)-(Val. Moy. Iso.)] / (Val. Moy. Iso.)
Val. Moy. Exp. = Valeur moyenne expérimentale Val. Moy. Iso. = Valeur moyenne de control isotypique
Anticorps Fournisseurs β1 Chemicon International (1 mg.mL-1) αVβ3 Chemicon International (1 mg.mL-1) α3β1 Chemicon International (1 mg.mL-1) α4β1 Chemicon International (1 mg.mL-1) α5β1 Chemicon International (1 mg.mL-1) α6β1 Chemicon International (1 mg.mL-1) Ig Contrôle Dako Cytomation (100 mg.mL-1) AC secondaire Dako Cytomation (1 g.mL-1)
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