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• W2796119448 abstract "Cancer ranks among the leading causes of death worldwide; this makes the development of novel and improved anticancer treatment a priority. Current oncological therapeutics aim to activate apoptosis to achieve disease control. However, cancer cells can adapt and become refractory to therapy by mutating and acquiring the ability to resist apoptotic stimuli. Therefore, development of more efficient therapies is a priority to improve cancer prognosis. Our laboratory has developed a cell permeable peptide called TAT-RasGAP317-326, which bears several anticancer properties. First, the RasGAP-derived peptide has the ability to inhibit metastatic progression by increasing cell adhesion and decreasing cell migration. Second, it was shown to specifically sensitize tumor cells to anticancer treatments such as chemotherapy and radiotherapy both in vitro and in vivo.In the present study, we provide evidences that TAT-RasGAP317-326 peptide can specifically sensitize cancer cells to chemotherapy-induced apoptosis independently of several key apoptotic regulators such as p53 and Bcl-2 family members, including Bax and Bak.We also report that this peptide possesses the capacity to directly kill a subset of cancer cell lines. Using pharmacologie and genetic inhibitions, we demonstrate that TAT-RasGAP3i7-326-induced death differs from known regulated forms of death. To understand how TAT-RasGAP3i7-326-death is controlled, we performed a genome-wide CRISPR knockout screening to assess the requirement of each essential gene. We found that specific potassium channels such as KCNQ5 in Raji cells and KCNN4 and KCNK5 in SKW6.4 cells are necessary for the peptide to kill those cells. We reveal that inhibition of these potassium channels prevents proper cytosolic access of TAT-RasGAP3i7-326, and other TAT-constructs. This ability to block extracellular compound to enter cells was assessed on several viruses. Preliminary data suggest that potassium channel blockade hampers the infectivity of specific pathogenic agents.By sheer serendipity, we uncover the antimicrobial property of TAT-RasGAP317-326. In vitro data demonstrate that the RasGAP-derived peptide is able to efficiently kill several pathogenic bacteria. We could validate in vivo using E. coli peritonitis model that TAT-RasGAP317-326 is a promising antibiotic peptide. --Le cancer est la deuxieme cause de mortalite dans le monde, apres les maladies cardiovasculaires. Pour combattre cette maladie, les traitements oncologiques traditionnels, tels que la radiotherapie et chimiotherapie, ont pour but d'induire la mort des cellules cancereuses par apoptose. Toutefois, ces cellules peuvent s'adapter et devenir refractaires aux therapies via l'accumulation de mutation leur permettant de resister aux stimuli apoptotiques. Le developpement de nouvelles therapies plus efficaces est donc une priorite afin d'ameliorer la survie des patients atteints de cancers.Notre laboratoire a developpe un peptide appele TAT-RasGAP317-326 possedant de multiples proprietes anti-cancers. Celui-ci a la capacite de reduire la formation de metastases en augmentant l'adherence des cellules et en bloquant la migration cellulaire. De plus, il a ete demontre que ce peptide a la faculte d'augmenter specifiquement dans les cellules cancereuses l'efficacite de la radiotherapie et chimiotherapie, a la fois in vitro et in vivo.Dans ce travail de these, nous avons montre que le peptide TAT-RasGAP317-326 est capable de sensibiliser les cellules cancereuses a l'apoptose induite par des agents chimiotherapeutiques, et ce independamment de proteines cles telles que p53 et des membres de la famille Bcl-2, dont Bax et Bak.Nous avons aussi montre que ce peptide pouvait tuer directement certaines lignees cancereuses. Par une approche d'inhibition, a la fois pharmacologique et genetique, nous avons demontre que la mort induite par TAT-RasGAP317-326 etait differente des formes connues de mort regulees. Pour comprendre le fonctionnement de la mort induite par ce peptide, nous avons crible le genome entier afin d'identifier les genes essentiels necessaires a sa toxicite. Nous avons mis en evidence l'implication de canaux a potassium, tels que KCNQ5 dans les cellules Raji ainsi que KCNN4 et KCNK5 dans les cellules SKW6.4. Nous avons etabli que le blocage de ces canaux a potassium empeche au peptide TAT- RasGAP3i7.326 mais aussi a d'autres molecules comportant la sequence TAT d'etre normalement internalises jusqu'au cytosol. La capacite d'empecher l'entree de composes extracellulaires represente un grand interet dans d'autres domaines de la biologie, tels que la virologie. Des donnees preliminaires montrent que l'inhibition de canaux a potassium permet de diminuer l'infectivite de plusieurs agents viraux pathogenes.Par serendipite, nous avons decouvert que TAT-RasGAP317-326 possede des proprietes antimicrobiennes. Nos donnees in vitro montrent qu'il est capable de tuer certaines bacteries hautement pathogenes. De plus, son efficacite in vivo a pu etre demontree grâce au modele de peritonite de la souris causee par E." @default.
• W2796119448 created "2018-04-13" @default.
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• W2796119448 date "2016-01-01" @default.
• W2796119448 modified "2023-09-24" @default.
• W2796119448 title "STRUCTURE-FUNCTION RELATIONSHIP OF THE URATE TRANSPORTER 5LC2A9 (GLUT9)" @default.
• W2796119448 hasPublicationYear "2016" @default.
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