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