期刊
ONCOTARGET
卷 7, 期 6, 页码 6693-6710出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.6793
关键词
cancer therapy; Annexin A1; cancer metabolism; HIF-1; induced essentiality
资金
- Deutsche Forschungsgemeinschaft (DFG)
- Deutsche Krebshilfe
- Bundesministerium fur Bildung und Forschung (BMBF)
- BMBF
- Senate of Berlin through the Berlin Institute of medical Systems Biology (BIMSB)
- Berlin Institute of Health (BIH)
- international NYU/MDC PhD-exchange program
- HMWK (UGMLC)
- DFG [TR84]
- BMBF (Progress/DZL)
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-1a. Via transcriptomics we identified a group of upregulated genes in HIF-1a-deficient cells and hypothesized that these genes confer survival upon HIF-1a loss. Strikingly, simultaneous knock-down of HIF-1a 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-1a/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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据