論文 - 詳細
| RRC ID | 77018 |
|---|---|
| 著者 | Rohwer N, Bindel F, Grimm C, Lin SJ, Wappler J, Klinger B, Blüthgen N, Du Bois I, Schmeck B, Lehrach H, de Graauw M, Goncalves E, Saez-Rodriguez J, Tan P, Grabsch HI, Prigione A, Kempa S, Cramer T. |
| タイトル | Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A. |
| ジャーナル | Oncotarget |
| 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. |
| 巻・号 | 7(6) |
| ページ | 6693-710 |
| 公開日 | 2016-2-9 |
| DOI | 10.18632/oncotarget.6793 |
| PII | 6793 |
| PMID | 26760764 |
| PMC | PMC4872743 |
| MeSH | Animals Annexin A1 / genetics Annexin A1 / metabolism* Cell Line, Tumor Cell Proliferation / physiology Female Heterografts Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Immunohistochemistry Mice Mice, Inbred NOD Mice, SCID RNA, Small Interfering / administration & dosage RNA, Small Interfering / genetics Stomach Neoplasms / metabolism* |
| IF | 5.168 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MKN28(RCB1000) |