石莼色素石莼素抑制 HIF-1 的激活和线粒体呼吸。
The Caulerpa pigment caulerpin inhibits HIF-1 activation and mitochondrial respiration.
机构信息
Department of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677, and Department of Biology, University of Mississippi, University, Mississippi 38677.
出版信息
J Nat Prod. 2009 Dec;72(12):2104-9. doi: 10.1021/np9005794.
The transcription factor hypoxia-inducible factor-1 (HIF-1) represents an important molecular target for anticancer drug discovery. In a T47D cell-based reporter assay, the Caulerpa spp. algal pigment caulerpin (1) inhibited hypoxia-induced as well as 1,10-phenanthroline-induced HIF-1 activation. The angiogenic factor vascular endothelial growth factor (VEGF) is regulated by HIF-1. Caulerpin (10 microM) suppressed hypoxic induction of secreted VEGF protein and the ability of hypoxic T47D cell-conditioned media to promote tumor angiogenesis in vitro. Under hypoxic conditions, 1 (10 microM) blocked the induction of HIF-1alpha protein, the oxygen-regulated subunit that controls HIF-1 activity. Reactive oxygen species produced by mitochondrial complex III are believed to act as a signal of cellular hypoxia that leads to HIF-1alpha protein induction and activation. Further mechanistic studies revealed that 1 inhibits mitochondrial respiration at electron transport chain (ETC) complex I (NADH-ubiquinone oxidoreductase). Under hypoxic conditions, it is proposed that 1 may disrupt mitochondrial ROS-regulated HIF-1 activation and HIF-1 downstream target gene expression by inhibiting the transport or delivery of electrons to complex III.
转录因子缺氧诱导因子-1（HIF-1）是抗癌药物发现的重要分子靶标。在 T47D 细胞报告基因检测中，石莼属海藻色素石莼素（1）抑制了缺氧诱导以及 1,10-菲咯啉诱导的 HIF-1 激活。血管内皮生长因子（VEGF）是一种血管生成因子，受 HIF-1 调节。石莼素（10 μM）抑制了缺氧诱导的分泌型 VEGF 蛋白的产生，以及缺氧 T47D 细胞条件培养基在体外促进肿瘤血管生成的能力。在缺氧条件下，1（10 μM）阻断了 HIF-1α蛋白的诱导，HIF-1α蛋白是控制 HIF-1 活性的氧调节亚基。线粒体复合物 III 产生的活性氧被认为是细胞缺氧的信号，导致 HIF-1α蛋白的诱导和激活。进一步的机制研究表明，1 抑制了线粒体呼吸在电子传递链（ETC）复合物 I（NADH-泛醌氧化还原酶）。在缺氧条件下，据推测 1 可能通过抑制电子向复合物 III 的转运或传递，破坏了线粒体 ROS 调节的 HIF-1 激活和 HIF-1 下游靶基因表达。
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