國家衛生研究院 NHRI:Item 3990099045/9649
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    题名: HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity
    其它题名: HIF-1-α links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity
    作者: Kuo, CY;Cheng, CT;Hou, P;Lin, YP;Ma, H;Chung, Y;Chi, K;Chen, Y;Li, W;Kung, HJ;Ann, DK
    贡献者: Institute of Molecular and Genomic Medicine
    摘要: Up-regulation of hypoxia-inducible factor-1alpha (HIF-1alpha), even in normoxia, is a common feature of solid malignancies. However, the mechanisms of increased HIF-1alpha abundance, and its role in regulating breast cancer plasticity are not fully understood. We have previously demonstrated that dimethyl-2-ketoglutarate (DKG), a widely used cell membrane-permeable alpha-ketoglutarate (alpha-KG) analogue, transiently stabilizes HIF-1alpha by inhibiting prolyl hydroxylase 2. Here, we report that breast cancer tumorigenicity can be acquired through prolonged treatment with DKG. Our results indicate that, in response to prolonged DKG treatment, mitochondrial respiration becomes uncoupled, leading to the accumulation of succinate and fumarate in breast cancer cells. Further, we found that an early increase in the oxygen flux rate was accompanied by a delayed enhancement of glycolysis. Together, our results indicate that these events trigger a dynamic enrichment for cells with pluripotent/stem-like cell markers and tumorsphere-forming capacity. Moreover, DKG-mediated metabolic reprogramming results in HIF-1alpha induction and reductive carboxylation pathway activation. Both HIF-1alpha accumulation and the tumor-promoting metabolic state are required for DKG-promoted tumor repopulation capacity in vivo. Our data suggest that mitochondrial adaptation to DKG elevates the ratio of succinate or fumarate to alpha-KG, which in turn stabilizes HIF-1alpha and reprograms breast cancer cells into a stem-like state. Therefore, our results demonstrate that metabolic regulation, with succinate and/or fumarate accumulation, governs the dynamic transition of breast cancer tumorigenic states and we suggest that HIF-1alpha is indispensable for breast cancer tumorigenicity.
    日期: 2016-06
    關聯: Oncotarget. 2016 Jun;7(23):34052-34069.
    Link to: http://dx.doi.org/10.18632/oncotarget.8570
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000377752100041
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84973664240
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