BCL-XL directly modulates RAS signalling to favour cancer cell stemness
| Autor: | Carné Trécesson, Sophie de, Souazé, Frédérique, Basseville, Agnès, Bernard, Anne-Charlotte, Pécot, Jessie, Lopez, Jonathan, Bessou, Margaux, Sarosiek, Kristopher A., Letai, Anthony, Barillé-Nion, Sophie, Valo, Isabelle, Coqueret, Olivier, Guette, Catherine, Campone, Mario, Gautier, Fabien, Juin, Philippe Paul |
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| Přispěvatelé: | Bernardo, Elizabeth, Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie et Biologie moléculaire [CH Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Dana-Farber Cancer Institute [Boston, USA], Harvard Medical School [Boston] (HMS), Département de Biopathologie [Angers], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Senescence Escape and Soluble Markers of Cancer Progression (CRCINA-ÉQUIPE 12), Dr S. de Carné Trécesson was supported by Institut National du Cancer, Dr J. Pécot by Ministère de la Recherche et de l’Enseignement Supérieur and Dr A. Basseville by Fondation de France. This work was supported by Canceropole Grand Ouest (CIC project 2010–2012, MATURE project 2017–18), ARC (R15083NN), Fondation de France (2015) and INCA PLBio (R12134NN) to PJ, Ligue Grand Ouest (R13137) to SCT and PJ and Fondation de France (2017) to AB., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Proteomics
Science bcl-X Protein Mice Nude [SDV.CAN]Life Sciences [q-bio]/Cancer Apoptosis Breast Neoplasms Article Mass Spectrometry Mice [SDV.CAN] Life Sciences [q-bio]/Cancer Cell Line Tumor Animals Humans lcsh:Science HMGA2 Protein Gene Expression Regulation Neoplastic Phenotype Drug Resistance Neoplasm MCF-7 Cells Neoplastic Stem Cells ras Proteins lcsh:Q Female Neoplasm Recurrence Local Proto-Oncogene Proteins c-fos Plasmids Signal Transduction |
| Zdroj: | Nature Communications Nature Communications, 2017, 8 (1), pp.1123. ⟨10.1038/s41467-017-01079-1⟩ Nature Communications, Vol 8, Iss 1, Pp 1-11 (2017) Nature Communications, Nature Publishing Group, 2017, 8 (1), pp.1123. ⟨10.1038/s41467-017-01079-1⟩ |
| ISSN: | 2041-1723 |
| Popis: | In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4-dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait. BCL-XL provides a survival advantage to cancer cells even in the absence of apoptotic pressures. In this study, the authors show that BCL-XL interacts with RAS in a BH4-dependent manner and regulates RAS-mediated activation of pathways involved in the stemness feature of breast cancer cells. |
| Databáze: | OpenAIRE |
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