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

Nadine Rohwer, Fabian Bindel, Christina Grimm, Suling J. Lin, Jessica Wappler, Bertram Klinger, Nils Bluethgen, Ilona Du Bois, Bernd Schmeck, Hans Lehrach, Marjo de Graauw, Emanuel Goncalves, Julio Saez-Rodriguez, Patrick Tan, Heike I. Grabsch, Alessandro Prigione, Stefan Kempa*, Thorsten Cramer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)

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-1a. Via transcriptomics we identified a group of upregulated genes in HIF-1a-deficient cells and hypothesized that these genes confer survival upon HIF-1a loss. Strikingly, simultaneous knock-down of HIF-1a 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-1a/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.
Original languageEnglish
Pages (from-to)6693-6710
JournalOncotarget
Volume7
Issue number6
DOIs
Publication statusPublished - 9 Feb 2016

Keywords

  • cancer therapy
  • Annexin A1
  • cancer metabolism
  • HIF-1
  • induced essentiality

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