Effect of low glutamine/glucose on hypoxia-induced elevation of hypoxia-inducible factor-1α in human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells
Effect of low glutamine/glucose on hypoxia-induced elevation of hypoxia-inducible factor-1α in human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells
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DOI：
10.1158/1078-0432.ccr-04-2530
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发表时间：
2005-07-01
影响因子：
11.5
通讯作者：
Lee, YJ
中科院分区：
文献类型：
--
作者：
Kwon, SJ;Lee, YJ
目的和实验设计：肿瘤微环境的特点是波动和慢性缺氧、低细胞外 pH 值和营养消耗的区域。尽管众所周知缺氧会刺激缺氧诱导因子 1 α (HIF-1 α) 的积累，但低细胞外 pH 值和营养消耗对缺氧上调 HIF-1 α 的作用尚不清楚。在这项研究中，人胰腺癌MiaPaCa-2和人前列腺癌DU-145细胞在存在或不存在葡萄糖、谷氨酰胺和/或丙酮酸的情况下暴露于缺氧。结果：我们观察到低葡萄糖和低谷氨酰胺，但不是低丙酮酸，在缺氧（0.1-1%氧）期间有效抑制HIF-1 α水平的升高。在蛋白酶抑制剂 MG-132 存在的情况下，无论氧张力如何，谷氨酰胺或葡萄糖的缺乏都会抑制 HIF-1 α 的积累。逆转录PCR分析数据显示，在缺氧条件下，不同浓度的谷氨酰胺或葡萄糖下，HIF-1 α mRNA的水平没有显着变化。 HIF-1 α 抑制量与蛋白质合成抑制成正比。结论：我们的数据表明，谷氨酰胺或葡萄糖剥夺通过破坏翻译过程而不是转录或蛋白酶体降解过程来抑制缺氧条件下 HIF-1 α 的积累。
Purpose and Experimental Design: Tumor microenvironment is characterized by regions of fluctuating and chronic hypoxia, low extracellular pH, and nutrient depletion. Although it is well known that hypoxia stimulates the accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha), the role of low extracellular pH and nutrient depletion on hypoxia up-regulation of HIF-1 alpha is not well known. In this study, human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells were exposed to hypoxia in the presence or absence of glucose, glutamine, and/or pyruvate.Results: We observed that low glucose and low glutamine, but not low pyruvate, effectively suppressed the elevation of HIF-1 alpha level during hypoxia (0.1-1% oxygen). Deprivation of glutamine or glucose inhibited the accumulation of HIF-1 alpha in the presence of MG-132, a protease inhibitor, regardless of oxygen tensions. Data from reverse transcription-PCR analysis revealed that the levels of HIF-1 alpha mRNA were not significantly changed at different concentrations of glutamine or glucose under hypoxia. The amount of HIF-1 alpha suppression was proportional to protein synthesis inhibition.Conclusions: Our data suggest that glutamine or glucose deprivation inhibits the accumulation of HIF-1 alpha under hypoxic conditions by disrupting translational processes rather than transcriptional or proteasomal degradation processes.