NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment
NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment
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DOI：
10.1073/pnas.1006646107
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发表时间：
2010-11-23
影响因子：
11.1
通讯作者：
Dewhirst, Mark W.
中科院分区：
文献类型：
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作者：
Moon, Eui Jung;Sonveaux, Pierre;Dewhirst, Mark W.
热疗（HT）是一种强有力的辅助治疗放疗和化疗，因为它会导致肿瘤复氧。然而，HT如何增强肿瘤氧合的详细分子机制尚未阐明。在这里，我们报告说，1小时的HT激活缺氧诱导因子-1（HIF-1）在肿瘤及其下游的目标，血管内皮生长因子（VEGF）和丙酮酸脱氢酶激酶1（PDK 1）。与HIF-1激活及其下游基因的上调一致，HT还增强肿瘤灌注/血管形成并降低氧消耗。因此，HT后肿瘤缺氧减少，表明这些生理变化有助于HT诱导的肿瘤复氧。由于HIF-1是肿瘤血管形成和代谢的有效调节剂，我们的研究结果表明，HIF-1通过反式激活其下游靶点在HT诱导的肿瘤再氧合中发挥作用。我们证明，NADPH氧化酶介导的活性氧的产生，作为一种机制，上调HIF-1后HT。此外，我们确定这一途径是由NADPH氧化酶-1通过ERK途径增加转录启动的。总之，这项研究确定，虽然HIF-1是一个很好的治疗靶点，但其抑制的时机需要优化，以实现最有益的结果时，它与其他治疗HT，放疗和化疗。
Hyperthermia (HT) is a strong adjuvant treatment with radiotherapy and chemotherapy because it causes tumor reoxygenation. However, the detailed molecular mechanisms of how HT enhances tumor oxygenation have not been elucidated. Here we report that 1 h of HT activates hypoxia-inducible factor-1 (HIF-1) in tumors and its downstream targets, vascular endothelial growth factor (VEGF) and pyruvate dehydrogenase kinase 1 (PDK1). Consistent with HIF-1 activation and up-regulation of its downstream genes, HT also enhances tumor perfusion/vascularization and decreases oxygen consumption. As a result, tumor hypoxia is reduced after HT, suggesting that these physiological changes contribute to HT-induced tumor reoxygenation. Because HIF-1 is a potent regulator of tumor vascularization and metabolism, our findings suggest that HIF-1 plays a role in HT-induced tumor reoxygenation by transactivating its downstream targets. We demonstrate that NADPH oxidase-mediated reactive oxygen species production, as a mechanism, upregulates HIF-1 after HT. Furthermore, we determine that this pathway is initiated by increased transcription of NADPH oxidase-1 through the ERK pathway. In conclusion, this study determines that, although HIF-1 is a good therapeutic target, the timing of its inhibition needs to be optimized to achieve the most beneficial outcome when it is combined with other treatments of HT, radiation, and chemotherapy.