Ion Channels as Promising Therapeutic Targets for Melanoma

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Rôle du récepteur Sigma-1 sur la régulation des canaux ioniques impliqués dans la carcinogenèse

Le récepteur sigma-1 est une protéine chaperonne active dans des tissus lésés. Le récepteur sigma-1 est principalement exprimé dans le cerveau et joue un rôle neuroprotecteur dans l ischémie ou les maladies neurodégénératives. Le récepteur sigma-1 est également exprimé dans des lignées cellulaires cancéreuses et des travaux récents suggèrent sa participation dans la prolifération et l apoptose. Cependant, son rôle dans la carcinogenèse reste à découvrir. Les canaux ioniques sont impliqués dans de nombreux processus physiologiques (rythme cardiaque, influx nerveux, ). Ces protéines membranaires émergent actuellement comme une nouvelle famille de cibles thérapeutiques dans les cancers. Au cours de ma thèse, j ai montré que le récepteur sigma-1 régule l activité du canal potassique voltage-dépendent hERG et du canal sodique voltage-dépendent Nav1.5 respectivement dans des cellules leucémiques et des cellules issues de cancer du sein. J ai également montré que le récepteur sigma-1, à travers son action sur l adressage du canal hERG, augmente l invasivité des cellules leucémiques en favorisant leur interaction avec le microenvironnement tumoral. Ces résultats mettent en évidence le rôle du récepteur sigma-1 sur la plasticité électrique des cellules cancéreuses et suggèrent l intérêt de cette protéine chaperonne comme cible thérapeutique potentielle pour limiter la progression tumorale.The sigma-1 receptor is a chaperone protein active in damaged tissues. The sigma-1 receptor is mainly expressed into brain and have a neuroprotective role in ischemia and neurodegenerative diseases. The sigma-1 receptor is also expressed into cancer cell lines and recent investigations suggest its involvement into proliferation and apoptosis. However, its role in carcinogenesis remains to delineating. Ion channels are involved in numerous physiological processes (heart beating, nervous influx, ). These membrane proteins currently emerge as a new class of therapeutic targets in cancer. During my thesis, I observed that the sigma-1 receptor regulates voltage-dependent potassium channel hERG and voltage-dependent sodium channel Nav1.5 activities respectively into leukemic and breast cancer cell lines. I also demonstrated that the sigma-1 receptor, through its action on hERG channel, increases leukemia invasiveness by promoting interaction with tumor microenvironment. These results highlight the role of the sigma-1 receptor on cancer cell electrical plasticity and suggest this chaperone protein as a potential therapeutic target to limit tumor progression.NICE-Bibliotheque electronique (060889901) / SudocSudocFranceF

Récepteur Sigma-1, canaux logiques et régulation du cycle cellulaire

Au cours du XXème siècle, le cancer s'est imposé comme un problème de santé publique majeur. C'est aujourd'hui la deuxième cause de mortalité en France. Face à un tel enjeu, de nombreuses voies de recherche sont explorées. Depuis une dizaine d'années, un nombre croissant d'études ont mis en évidence l'implication des canaux ioniques dans les processus de migration, de prolifération et de mort cellulaire. Si le rôle précis que jouent les canaux dans ces phénomènes reste encore à déterminer, leur intérêt dans le cadre du cancer ne fait plus guère de doute. Certaines de ces études soulignent plus spécifiquement l'implication des canaux K+ et Cl- responsables de la régulation du volume (RVD). Une autre protéine, le récepteur sigma-1, commence également à attirer l'attention des chercheurs. C'est une protéine de 26 kDa, principalement localisée au niveau des membranes du RE et de la MP, son plus proche parent est une C8-C7 stérol isomérase de levure. Le récepteur sigma-1 a la particularité d'être surexprimé dans les cellules tumorales. Cependant, la raison d'être de cette surexpression demeure énigmatique. Soriani a récemment mis en évidence l'inhibition de canaux K+ par le récepteur sigma-1 (Soriani O et al, 1998). Aussi, nous avons décidé d'explorer la possibilité de relations entre le récepteur sigma-1, les canaux ioniques (K+ et Cl-) et la prolifération des cellules tumorales. A partir de cellules issues de tumeurs pulmonaires (SCLC) et de leucémie T aiguë (Jurkat), les travaux réalisés au cours de cette thèse ont permis de démontrer, pour la première fois, que l'activation pharmacologique du récepteur sigma-1 avec des ligands spécifiques bloque la prolifération des cellules en phase G1 de leur cycle cellulaire. Cette inhibition de la prolifération se traduit moléculairement par l'augmentation du niveau d'expression de p27kip1, un inhibiteur du cycle cellulaire, et une baisse du niveau d'expression de cycline A, une protéine clef de phase S. Nos résultats indiquent que cet arrêt repose sur l'inhibition de deux types de canaux impliqués dans la régulation du volume cellulaire : des canaux K+ dépendants du potentiel (Kv) et des canaux Cl- de type ICl,swell. C'est la première fois que l'inhibition d'une conductance Cl- par le récepteur sigma-1 est démontrée. Par ailleurs, la surexpression du récepteur sigma-1 dans des cellules HEK modifie les propriétés cinétiques de leur conductance ICl,swell, entraînant un ralentissement des processus de régulation du volume. Ainsi, lorsque ces cellules subissent des stress apoptotiques, l'AVD (Apoptotic Volume Decrease) est partiellement inhibé et les cellules sont protégées de l'apoptose. Cet effet est de nature à expliquer la surexpression du récepteur sigma-1 dans les tumeurs.During the 20th century, cancer has emerged as a major public health problem. Nowadays, it's the second cause of mortality in France. Faced with such a stake, many research pathways are curently explored. In the last decade, a growing number of studies have put in the light the implication of ionic channels in cellular migration, proliferation and death. If the precise function of ionic channels in these phenomenon is still unclear, there's no doubt about their interest within the framework of cancer. Some of these studies underline more specifically the implication of the K+ and Cl- channels which are presiding to cell volume regulation (RVD). An other protein, the sigma-1 receptor, is begining to draw the attention of researchers. It's a protein of 26 kDa, mostly localised at the RE and MP membranes and only related to a yeast C8-C7 sterol isomerase. Interestingly, the sigma-1 receptor is overexpressed in tumour cells. However, the reason of this overexpression remains enigmatic. Recently, Soriani has shown that sigma-1 receptor inhibit K+ channels (Soriani et al, 1998). That's why we decided to explore a putative link between sigma-1 receptor, ionic channels (K+ et Cl-) and tumour cell proliferation. In this work, we used pulmonary tumour cells (SCLC) and acute T-leucemic cells (Jurkat). For the first time, we have demonstrated that pharmacological activation of the sigma-1 receptor with specific ligands arrests cell proliferation in the G1 phase of the cell-cycle. This inhibition of proliferation is underlined by an increase in p27kip1 (a cell cycle inhibitor) and a decrease in cyclin A (a S phase key protein) expression levels. Our results indicate that this arrest is based on the inhibition of two famillies of ionic channels crucials for cell volume regulation : voltage-dependant K+ channels (Kv) and Cl- channels of the ICl,swell family. It's the first time that an inhibition of Cl- channels by sigma-1 receptors is demonstrated. In other respects, sigma-1 receptor overexpression in HEK cells alters the kinetic properties of ICl,swell leading to a slow down of volume regulation process. Therefore, when cells are submitted to an apoptotic stress, the AVD (Apoptotic Volume Decrease) is partially inhibited and cells are protected against apoptosis. Those results might explain the overexpression of the sigma-1 receptor in tumour's cells.NICE-BU Sciences (060882101) / SudocSudocFranceF

Cardiac Glycosides as Senolytic Compounds

International audienceThe identification of senolytics, compounds that eliminate senescent cells, is presently a key priority given their therapeutic promise in cancer and aging-associated diseases. Two recent papers by Triana-Martínez et al. and Guerrero et al. report the senolytic activity of cardiac glycosides (CGs) and their efficacy in these pathophysiological contexts

Interplay Between Ion Channels and the Wnt/β-Catenin Signaling Pathway in Cancers

International audienceIncreasing evidence point out the important roles of ion channels in the physiopathology of cancers, so that these proteins are now considered as potential new therapeutic targets and biomarkers in this disease. Indeed, ion channels have been largely described to participate in many hallmarks of cancers such as migration, invasion, proliferation, angiogenesis, and resistance to apoptosis. At the molecular level, the development of cancers is characterised by alterations in transduction pathways that control cell behaviors. However, the interactions between ion channels and cancer-related signaling pathways are poorly understood so far. Nevertheless, a limited number of reports have recently addressed this important issue, especially regarding the interaction between ion channels and one of the main driving forces for cancer development: the Wnt/b-catenin signaling pathway. In this review, we propose to explore and discuss the current knowledge regarding the interplay between ion channels and the Wnt/b-catenin signaling pathway in cancers

Contribution of changes in the chloride driving force to the fading of I GABA in frog melanotrophs

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Population-based meta-heuristic for active modules identification

International audienceThe identification of condition specific gene sets from transcriptomic experiments has important biological applications, ranging from the discovery of altered pathways between different phenotypes to the selection of disease-related biomarkers. Statistical approaches using only gene expression data are based on an overly simplistic assumption that the genes with the most altered expressions are the most important in the process under study. However, a phenotype is rarely a direct consequence of the activity of a single gene, but rather reflects the interplay of several genes to perform certain molecular processes. Many methods have been proposed to analyze gene activity in the light of our knowledge about their molecular interactions. We propose, in this article, a population-based meta-heuristics based on new crossover and mutation operators. Our method achieves state of the art performance in an independent simulation experiment used in other studies. Applied to a public transcriptomic dataset of patients afflicted with Hepatocellular carcinoma, our method was able to identify significant modules of genes with meaningful biological relevance

Population-based meta-heuristic for active modules identification

International audienceThe identification of condition specific gene sets from transcriptomic experiments has important biological applications, ranging from the discovery of altered pathways between different phenotypes to the selection of disease-related biomarkers. Statistical approaches using only gene expression data are based on an overly simplistic assumption that the genes with the most altered expressions are the most important in the process under study. However, a phenotype is rarely a direct consequence of the activity of a single gene, but rather reflects the interplay of several genes to perform certain molecular processes. Many methods have been proposed to analyze gene activity in the light of our knowledge about their molecular interactions. We propose, in this article, a population-based meta-heuristics based on new crossover and mutation operators. Our method achieves state of the art performance in an independent simulation experiment used in other studies. Applied to a public transcriptomic dataset of patients afflicted with Hepatocellular carcinoma, our method was able to identify significant modules of genes with meaningful biological relevance

Identification of active modules in interaction networks using node2vec network embedding

The identification of condition-specific gene sets from transcriptomic experiments is important to reveal regulatory and signaling mechanisms associated with a given cellular response. Statistical approaches using only expression data allow the identification of genes whose expression is most altered between different conditions. However, a phenotype is rarely a direct consequence of the activity of a single gene, but rather reflects the interplay of several genes to carry out certain molecular processes. Many methods have been proposed to analyze the activity of genes in light of our knowledge of their molecular interactions. However, existing methods have many limitations that make them of limited use to biologists: they detect modules that are too large, too small, or they require the users to specify a priori the size of the modules they are looking for. We propose AMINE (Active Module Identification through Network Embedding), an efficient method for the identification of active modules. Experiments carried out on artificial data sets show that the results obtained are more reliable than many available methods. Moreover, the size of the modules to be identified is not a fixed parameter of the method and does not need to be specified; rather, it adjusts according to the size of the modules to be found. The applications carried out on real datasets show that the method enables to find important genes already highlighted by approaches solely based on gene variations, but also to identify new groups of genes of high interest. In addition, AMINE method can be used as a web service on your own data (http://amine.i3s.unice.fr)