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Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia.
Journal of Pineal Research ( IF 10.3 ) Pub Date : 2010-05-08 , DOI: 10.1111/j.1600-079x.2009.00742.x
Shi-Young Park 1 , Won-Jun Jang , Eui-Yeun Yi , Ji-Yeong Jang , Yunjin Jung , Joo-Won Jeong , Yung-Jin Kim
Affiliation  

Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases, resulting in hypoxia in the cancer cells. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. The key regulator of hypoxia-induced angiogenesis is the transcription factor known as hypoxia-inducible factor (HIF)-1. HIF-1alpha is stabilized by hypoxia-induced reactive oxygen species (ROS) and enhances the expression of several types of hypoxic genes, including that of the angiogenic activator known as vascular endothelial cell growth factor (VEGF). In this study, we found that melatonin, a small lipophilic molecule secreted primarily by the pineal gland, destabilizes hypoxia-induced HIF-1alpha protein levels in the HCT116 human colon cancer cell line. This destabilization of HIF-1alpha resulted from the antioxidant activity of melatonin against ROS induced by hypoxia. Moreover, under hypoxia, melatonin suppressed HIF-1 transcriptional activity, leading to a decrease in VEGF expression. Melatonin also blocked in vitro tube formation and invasion and migration of human umbilical vein endothelial cells induced by hypoxia-stimulated conditioned media of HCT116 cells. These findings suggest that melatonin could play a pivotal role in tumor suppression via inhibition of HIF-1-mediated angiogenesis.

中文翻译:

褪黑素通过抑制缺氧条件下的HIF-1alpha稳定来抑制肿瘤血管生成。

血管生成是肿瘤进展的重要介质。随着肿瘤的扩大,与现有血管供应的扩散距离增加,导致癌细胞缺氧。肿瘤块的持续扩张需要新的血管形成,以向迅速增殖的肿瘤细胞提供充足的氧气和营养。缺氧诱导的血管生成的关键调节因子是转录因子,称为低氧诱导因子(HIF)-1。HIF-1alpha由低氧诱导的活性氧(ROS)稳定,并增强了几种类型的低氧基因的表达,包括称为血管内皮细胞生长因子(VEGF)的血管生成激活剂的表达。在这项研究中,我们发现褪黑激素是一种主要由松果体分泌的小亲脂分子,使HCT116人结肠癌细胞系中缺氧诱导的HIF-1alpha蛋白水平不稳定。HIF-1alpha的这种不稳定是由褪黑素对缺氧诱导的ROS的抗氧化活性造成的。此外,在缺氧条件下,褪黑素抑制了HIF-1转录活性,导致VEGF表达下降。褪黑素还阻断了缺氧刺激的HCT116细胞条件培养基诱导的体外管形成以及人脐静脉内皮细胞的侵袭和迁移。这些发现表明褪黑激素可以通过抑制HIF-1介导的血管生成在肿瘤抑制中发挥关键作用。褪黑素抑制HIF-1转录活性,导致VEGF表达下降。褪黑素还阻断了由缺氧刺激的HCT116细胞条件培养基诱导的人脐静脉内皮细胞的体外管形成以及侵袭和迁移。这些发现表明褪黑激素可以通过抑制HIF-1介导的血管生成在肿瘤抑制中发挥关键作用。褪黑素抑制HIF-1转录活性,导致VEGF表达下降。褪黑素还阻断了缺氧刺激的HCT116细胞条件培养基诱导的体外管形成以及人脐静脉内皮细胞的侵袭和迁移。这些发现表明褪黑激素可以通过抑制HIF-1介导的血管生成在肿瘤抑制中发挥关键作用。
更新日期:2010-01-25
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