Rohwer, N, Bindel, F, Grimm, C et al. (15 more authors) (2015) Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A. Oncotarget, 7 (6). pp. 6693-6710.
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015, The Author(s). Creative Commons Attribution 3.0 License. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Pathology & Tumour Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Nov 2016 12:09 |
Last Modified: | 04 Nov 2016 12:09 |
Published Version: | https://doi.org/10.18632/oncotarget.6793 |
Status: | Published |
Publisher: | Impact Journals |
Identification Number: | 10.18632/oncotarget.6793 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:105719 |