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| Item Type: | Article |
|---|---|
| Title: | Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A |
| Creators Name: | Rohwer, N., Bindel, F., Grimm, C., Lin, S.J., Wappler, J., Klinger, B., Blüthgen, N., Du Bois, I., Schmeck, B., Lehrach, H., de Graauw, M., Goncalves, E., Saez-Rodriguez, J., Tan, P., Grabsch, H.I., Prigione, A., Kempa, S. and Cramer, T. |
| 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{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. |
| Keywords: | Cancer Therapy, Annexin A1, Cancer Metabolism, HIF-1, Induced Essentiality, Animals, Mice |
| Source: | Oncotarget |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Volume: | 7 |
| Number: | 6 |
| Page Range: | 6693-6710 |
| Date: | 29 December 2015 |
| Official Publication: | https://doi.org/10.18632/oncotarget.6793 |
| PubMed: | View item in PubMed |
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