Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A


  • N. Rohwer
  • F. Bindel
  • C. Grimm
  • S.J. Lin
  • J. Wappler
  • B. Klinger
  • N. Blüthgen
  • I. Du Bois
  • B. Schmeck
  • H. Lehrach
  • M. de Graauw
  • E. Goncalves
  • J. Saez-Rodriguez
  • P. Tan
  • H.I. Grabsch
  • A. Prigione
  • S. Kempa
  • T. Cramer


  • Oncotarget


  • Oncotarget 7 (6): 6693-6710


  • 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-1{alpha}. Via transcriptomics we identified a group of upregulated genes in HIF-1{alpha}-deficient cells and hypothesized that these genes confer survival upon HIF-1{alpha} loss. Strikingly, simultaneous knock-down of HIF-1{alpha} 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-1{alpha}/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.