Metabolic consequences of HIF silencing in a triple negative human breast cancer xenograft.
Metabolic consequences of HIF silencing in a triple negative human breast cancer xenograft.
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DOI：
10.18632/oncotarget.24569
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发表时间：
2018-03-16
期刊：
影响因子：
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通讯作者：
Bhujwalla, Zaver M
中科院分区：
文献类型：
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作者：
Bharti, Santosh K;Mironchik, Yelena;Bhujwalla, Zaver M
低氧常见于肿瘤中，导致低氧诱导因子(HIF)的稳定。这些因子通过转录激活允许细胞适应低氧的基因。在癌症中，缺氧和HIF与侵袭、转移以及对化疗和放射治疗的抵抗力增加有关。在这里，我们使用体内肿瘤的非侵入性质子磁共振波谱成像(1H MRSI)和肿瘤提取物的高分辨率1HMRS，表征了在MDA-MB-231三阴性人乳腺癌移植瘤中单独或联合沉默HIF-1α和HIF-2α的代谢后果。所有三种亚系的肿瘤生长速度都显著降低。我们确定了HIF的新代谢靶点，并证明了分别沉默HIF-1α和HIF-2α对其中一些靶点的不同影响。这些数据扩大了我们对HIF调控的代谢途径的理解，这可能为癌细胞对低氧的适应性代谢反应提供新的见解。这样的见解可能会导致基于新陈代谢的三阴性乳腺癌治疗靶点的出现。
Hypoxia is frequently encountered in tumors and results in the stabilization of hypoxia inducible factors (HIFs). These factors transcriptionally activate genes that allow cells to adapt to hypoxia. In cancers, hypoxia and HIFs have been associated with increased invasion, metastasis, and resistance to chemo and radiation therapy. Here we have characterized the metabolic consequences of silencing HIF-1alpha and HIF-2alpha singly or combined in MDA-MB-231 triple negative human breast cancer xenografts, using non-invasive proton magnetic resonance spectroscopic imaging (1H MRSI) of in vivo tumors, and high-resolution 1H MRS of tumor extracts. Tumors from all three sublines showed a significant reduction of growth rate. We identified new metabolic targets of HIF, and demonstrated the divergent consequences of silencing HIF-1alpha and HIF-2alpha individually on some of these targets. These data expand our understanding of the metabolic pathways regulated by HIFs that may provide new insights into the adaptive metabolic response of cancer cells to hypoxia. Such insights may lead to novel metabolism based therapeutic targets for triple negative breast cancer.