Tumour-selective apoptosis : identification of NMHCIIa as novel death receptor interactor regulating the response to TRAIL

• Main Author: Schulz, Cathrin
• Other Authors: Strasbourg
• Language: en
• Published: 2012
• Subjects: TRAIL; DISC; Cellules normales; Apoptose; Spécifique de tumeur; Cytosquelette; Non-muscle myosin heavy chain IIa; NMHCIIa; Normal cells; Apoptosis; Tumour-selective; Cytoskeleton; 572.8; 616.99
• Online Access: http://www.theses.fr/2012STRAJ126/document

La cytokine TRAIL est un candidat anticancéreux qui induit la mort spécifique de cellules tumorales. La liaison de TRAIL à ses récepteurs (DR) permet de former le complexe DISC qui induit la mort cellulaire. La raison de la mort sélective des cellules tumorales induite par TRAIL est inconnue. Nous avons découvert des partenaires de DR: chaînes lourdes de myosine IIa, IIb (NMHCIIa, NMHCIIb), chaîne légère régulatrice de myosine (MLC2) et ß-actine. Dans les cellules tumorales, la liaison de TRAIL abroge l'interaction NMHCII/DR, et DISC est activé. Au contraire, dans les cellules normales, l'interaction NMHCII/DR persiste et l'activation de DISC est incomplète. Affaiblir l'interaction NMHCII/DR par des inhibiteurs chimiques ou diminuer NMHCIIa permet d'augmenter l'apoptose liée à TRAIL. L'interaction réduite NMHCII/DR induit des niveaux altérés de phospho-MLC2 et de kinases régulant MLC2. Nous proposons que la résistance de cellules normales à TRAIL soit basée sur l'interaction DR/cytosquelette, déficiente dans des tumeurs. NMHCII étant aussi impliqué dans l'adhésion/migration cellulaire, il serait intéressant d'étudier les fonctions de NMHCII/DISC dans le détachement cellulaire, afin de mieux comprendre la résistance à TRAIL de certains cancers. === The cytokine TRAIL is a promising cancer therapeutic candidate as it induces apoptosis selectively in transformed cells. TRAIL-induced clustering of its receptors (DR) is essential for the DISC complex formation, which induces cell death. The mechanism for TRAIL’s tumour selective effect is largely unknown. We identified the cytoskeleton proteins non-muscle myosin heavy chain IIa, IIb (NMHCIIa, NMHCIIb), myosin regulatory light chain (MLC2) and ß-actin as novel DR-interactors. An initially weak and TRAIL-induced abrogation of NMHCII/DR interaction correlated with efficient DISC formation in tumour cells. In contrast, a robust NMHCII/DR interaction that was sustained upon TRAIL stimulus was accompanied by incomplete DISC arrangement. Weakening the NMHCII/DR interaction in normal cells using chemical inhibitors enhanced TRAIL-induced apoptosis. Intriguingly, siRNA-mediated NMHCIIa- but not NMHCIIb depletion potently released TRAIL resistance in normal cells and influenced DISC composition. Reduced NMHCII/DR interaction in transformed cells was characterised by diminished MLC2 phosphorylation and altered protein expression of upstream regulatory kinases. Our results suggest that normal cell resistance to TRAIL-apoptosis is based on the interaction of cytoskeleton components with DR that is impaired upon transformation. Since NMHCII function in cell adhesion and migration, it will be interesting to study possible roles of the interaction in cell detachment and altered TRAIL sensitivity; moreover this link may provide clues as to the cause of TRAIL resistance in some cancers.