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

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

SUBMITTER: Rohwer N 

PROVIDER: S-EPMC4872743 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature