Sirt1 protects from K‐Ras‐driven lung carcinogenesis |
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| Authors: | Luis Filipe Costa‐Machado Roberto Martín‐Hernández Miguel Ángel Sanchez‐Luengo Katharina Hess Claudia Vales‐Villamarin Marta Barradas Cian Lynch Daniel de la Nava Alberto Diaz‐Ruiz Rafael de Cabo Marta Cañamero Lola Martinez Marta Sanchez‐Carbayo Daniel Herranz Manuel Serrano Pablo J Fernandez‐Marcos |
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| Affiliation: | 1. Bioactive Products and Metabolic Syndrome Group – BIOPROMET, Madrid Institute for Advanced Studies ‐ IMDEA Food, CEI UAM+CSIC, Madrid, Spain;2. GENYAL Nutrigenomic Platform, Madrid Institute for Advanced Studies ‐ IMDEA Food, CEI UAM+CSIC, Madrid, Spain;3. Flow Cytometry Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain;4. Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain;5. Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain;6. Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA;7. Nutritional Interventions Group, Precision Nutrition and Aging, Madrid Institute for Advanced Studies ‐ IMDEA Food, CEI UAM+CSIC, Madrid, Spain;8. Histopathology Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain;9. Pathology and Tissue Analysis, Pharma Research and Early Development, Roche Innovation Centre, Munich, Germany;10. Translational Oncology Lab, Lucio Lascaray Research Center, University of the Basque Country, Vitoria‐Gasteiz, Spain;11. Rutgers Cancer Institute of New Jersey and Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA;12. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain |
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| Abstract: | The NAD+‐dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non‐small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K‐RAS. Therefore, we investigated the effect of SIRT1 on K‐RAS‐driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K‐RAS in a MEK and PI3K‐dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K‐RasG12V‐driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1‐Tg pneumocytes, isolated shortly after K‐RasG12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K‐RAS‐driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1–K‐RAS axis could be a therapeutic target for NSCLCs. |
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| Keywords: | K‐RAS non‐small cell lung carcinoma SIRT1 |
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