Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia-inducible factor-1beta (HIF-1beta): evidence of an anabolic role for the HIF-1 pathway.
Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia-inducible factor-1beta (HIF-1beta): evidence of an anabolic role for the HIF-1 pathway.
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通过 HEPA-1 野生型肿瘤和缺乏缺氧诱导因子 1β (HIF-1β) 的肿瘤体内磁共振研究检测到的代谢变化：HIF-1 途径合成代谢作用的证据。
作者：
J. Griffiths;P. Mcsheehy;S. Robinson;H. Troy;Yuen;R. Leek;K. Williams;I. Stratford;A. Harris;M. Stubbs
缺氧诱导因子-1（HIF-1）调节许多对肿瘤生长具有潜在重要性的途径，包括血管生成和糖酵解。大多数注意力集中在其在缺氧反应中的作用，但HIF-1也在许多肿瘤中组成型表达。为了分析该途径在体内的作用，我们使用磁共振（MR）方法和补充技术来监测源自HEPA-1小鼠肝癌系的肿瘤的代谢变化，这些肝癌系是野生型（WT）或缺氧诱导转录因子HIF-1 β（c4）缺陷的。c4肿瘤的生长明显慢于WT肿瘤（P <0.05），但检查的大小相似（0.4 - 0.6 g）。在这些研究中使用的肿瘤大小，没有观察到血管分布的差异，测量的与肿瘤血流、血管分布和氧合相关的MR参数表明两种肿瘤类型之间没有显著差异。出乎意料的是，c4肿瘤的ATP含量比WT肿瘤中低约5倍[在肿瘤提取物中测量（P <0.001）和通过代谢成像测量（P <0.05）]。非侵入性（31）P磁共振波谱显示两种肿瘤类型的三磷酸核苷/P（i）比值相似，因此c4肿瘤的低ATP含量不是由受损的细胞生物能量学引起的（或原因）。相反，甘氨酸，一种从头嘌呤形成的必需前体，在c4肿瘤中显著降低（P <0.05），表明突变肿瘤细胞中ATP合成受损。支持这一假设的证据来自c4肿瘤中甜菜碱、磷酸胆碱和胆碱的浓度显著较低（P <0.05）;这些是甘氨酸合成替代途径中的中间产物。乳酸盐或葡萄糖含量无显著差异。与磷脂膜的代谢转换相关的磷酸二酯的MR共振在WT肿瘤中显著低于c4肿瘤，无论是在体内（P <0.05）还是在提取物中（P <0.01）。我们提出，在c4肿瘤中的葡萄糖转运蛋白和糖酵解酶的基因的表达上调的损失减少了甘氨酸的形成，这是ATP合成的必要前体，从而导致c4肿瘤的低ATP含量。总之，这些数据表明，这些肿瘤细胞中HIF-1通路的中断损害了细胞合成所需的合成代谢前体的供应。他们提出了可能通过阻断HIF-1功能的治疗来改变的潜在生化靶点。
Hypoxia-inducible factor-1 (HIF-1) regulates many pathways potentially important for tumor growth, including angiogenesis and glycolysis. Most attention has focused on its role in the response to hypoxia, but HIF-1 is also constitutively expressed in many tumors. To analyze the role of this pathway in vivo, we used magnetic resonance (MR) methods and complementary techniques to monitor metabolic changes in tumors derived from HEPA-1 mouse hepatoma lines that were either wild type (WT) or deficient in hypoxia-inducible transcription factor HIF-1beta (c4). The c4 tumors grew significantly more slowly than the WT tumors (P < 0.05), but were examined at a similar size (0.4-0.6 g). At the tumor size used in these studies, no differences in vascularity were observed, and MR parameters measured that related to tumor blood flow, vascularity, and oxygenation demonstrated no significant differences between the two tumor types. Unexpectedly, the ATP content of the c4 tumor was approximately 5 times less than in the WT tumor [measured in tumor extracts (P < 0.001) and by metabolic imaging (P < 0.05)]. Noninvasive (31)P MR spectroscopy showed that the nucleoside triphosphate/P(i) ratio of the two tumor types was similar, so the low ATP content of the c4 tumors was not caused by (or a cause of) impaired cellular bioenergetics. Rather, glycine, an essential precursor for de novo purine formation, was significantly lower in the c4 tumors (P < 0.05), suggesting that ATP synthesis was impaired in the mutant tumor cells. Supporting evidence for this hypothesis came from the significantly lower concentrations of betaine, phosphocholine, and choline in the c4 tumors (P < 0.05); these are intermediates in an alternative pathway for glycine synthesis. No significant differences were seen in lactate or glucose content. MR resonances from phosphodiesters, which relate to the metabolic turnover of phospholipid membranes, were significantly lower in the WT tumors than in the c4 tumors, both in vivo (P < 0.05) and in extracts (P < 0.01). We propose that loss of up-regulation of expression of the genes for glucose transporters and glycolytic enzymes in the c4 tumors decreased formation of glycine, an essential precursor of ATP synthesis, and thus caused the low ATP content of the c4 tumors. In summary, these data suggest that disruption of the HIF-1 pathway in these tumor cells impairs the supply of anabolic precursors required for cell synthesis. They suggest potential biochemical targets that may be modified by therapy blocking HIF-1 function.
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影响因子：
11.2
作者：
Janice M. Y. Brown;A. Giaccia
通讯作者：
Janice M. Y. Brown;A. Giaccia
影响因子：
--
作者：
GILLIES, RJ;LIU, Z;BHUJWALLA, Z
通讯作者：
BHUJWALLA, Z
影响因子：
10.5
作者：
G. Semenza
通讯作者：
G. Semenza
DOI：
10.1073/pnas.92.12.5510
发表时间：
1995-06-06
影响因子：
11.1
作者：
WANG, GL;JIANG, BH;SEMENZA, GL
通讯作者：
SEMENZA, GL
影响因子：
5.8
作者：
Semenza, GL
通讯作者：
Semenza, GL