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Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A.
Rohwer, Nadine; Bindel, Fabian; Grimm, Christina; Lin, Suling J; Wappler, Jessica; Klinger, Bertram; Blüthgen, Nils; Du Bois, Ilona; Schmeck, Bernd; Lehrach, Hans; de Graauw, Marjo; Goncalves, Emanuel; Saez-Rodriguez, Julio; Tan, Patrick; Grabsch, Heike I; Prigione, Alessandro; Kempa, Stefan; Cramer, Thorsten.
Afiliación
  • Rohwer N; Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité, Berlin, Germany.
  • Bindel F; German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Grimm C; German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Lin SJ; Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
  • Wappler J; Max-Planck-Institut for Molecular Genetics, Berlin, Germany.
  • Klinger B; Duke-NUS Graduate Medical School, Singapore.
  • Blüthgen N; GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
  • Du Bois I; Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • Schmeck B; Integrative Research Institute (IRI) for The Life Sciences and Institute for Theoretical Biology, Humboldt-Universität Berlin, Berlin, Germany.
  • Lehrach H; Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • de Graauw M; Integrative Research Institute (IRI) for The Life Sciences and Institute for Theoretical Biology, Humboldt-Universität Berlin, Berlin, Germany.
  • Goncalves E; Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University, Marburg, Germany.
  • Saez-Rodriguez J; Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University, Marburg, Germany.
  • Tan P; Max-Planck-Institut for Molecular Genetics, Berlin, Germany.
  • Grabsch HI; Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Amsterdam, The Netherlands.
  • Prigione A; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, United Kingdom.
  • Kempa S; Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Faculty of Medicine, Aachen, Germany.
  • Cramer T; Duke-NUS Graduate Medical School, Singapore.
Oncotarget ; 7(6): 6693-710, 2016 Feb 09.
Article en En | MEDLINE | ID: mdl-26760764
Despite the approval of numerous molecular targeted drugs, long-term antiproliferative efficacy is rarely achieved and therapy resistance remains a central obstacle of cancer care. Combined inhibition of multiple cancer-driving pathways promises to improve antiproliferative efficacy. HIF-1 is a driver of gastric cancer and considered to be an attractive target for therapy. We noted that gastric cancer cells are able to functionally compensate the stable loss of HIF-1α. Via transcriptomics we identified a group of upregulated genes in HIF-1α-deficient cells and hypothesized that these genes confer survival upon HIF-1α loss. Strikingly, simultaneous knock-down of HIF-1α and Annexin A1 (ANXA1), one of the identified genes, resulted in complete cessation of proliferation. Using stable isotope-resolved metabolomics, oxidative and reductive glutamine metabolism was found to be significantly impaired in HIF-1α/ANXA1-deficient cells, potentially explaining the proliferation defect. In summary, we present a conceptually novel application of stable gene inactivation enabling in-depth deconstruction of resistance mechanisms. In theory, this experimental approach is applicable to any cancer-driving gene or pathway and promises to identify various new targets for combination therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Anexina A1 / Subunidad alfa del Factor 1 Inducible por Hipoxia Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Anexina A1 / Subunidad alfa del Factor 1 Inducible por Hipoxia Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos