Research Papers:
Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A
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Nadine Rohwer1,2,3,*, Fabian Bindel4,*, Christina Grimm5, Suling J. Lin6, Jessica Wappler13, Bertram Klinger7,8, Nils Blüthgen7,8, Ilona Du Bois9, Bernd Schmeck9, Hans Lehrach5, Marjo de Graauw10, Emanuel Goncalves11, Julio Saez-Rodriguez12, Patrick Tan6, Heike I. Grabsch13, Alessandro Prigione14, Stefan Kempa4,#, Thorsten Cramer15,#
1Hepatologie und Gastroenterologie, Campus Virchow-Klinikum, Charité, Berlin, Germany
2German Cancer Consortium (DKTK), Heidelberg, Germany
3German Cancer Research Center (DKFZ), Heidelberg, Germany
4Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
5Max-Planck-Institut for Molecular Genetics, Berlin, Germany
6Duke-NUS Graduate Medical School, Singapore
7Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
8Integrative Research Institute (IRI) for the Life Sciences and Institute for Theoretical Biology, Humboldt-Universität Berlin, Berlin, Germany
9Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University, Marburg, Germany
10Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Amsterdam, The Netherlands
11European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, United Kingdom
12Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Faculty of Medicine, Aachen, Germany
13GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands
14Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
15Molecular Tumor Biology, Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Aachen, Germany
*These authors contributed equally to this work
#These authors jointly directed this work
Correspondence to:
Thorsten Cramer, e-mail: [email protected]
Stefan Kempa, e-mail: [email protected]
Keywords: cancer therapy, Annexin A1, cancer metabolism, HIF-1, induced essentiality
Received: June 29, 2015 Accepted: December 08, 2015 Published: December 29, 2015
ABSTRACT
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.