The Caulerpa pigment caulerpin inhibits HIF-1 activation and mitochondrial respiration.

Abstract

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.

• Authors: Yang Liu, J Brian Morgan, Veena Coothankandaswamy, Rui Liu, Mika B Jekabsons, Fakhri Mahdi, Dale G Nagle, Yu-Dong Zhou
• Journal: Journal of natural products (J Nat Prod) Vol. 72 Issue 12 Pg. 2104-9 (Dec 2009) ISSN: 1520-6025 [Electronic] United States
• PMID: 19921787 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Coloring Agents
• Hypoxia-Inducible Factor 1
• Indoles
• Vascular Endothelial Growth Factor A
• caulerpin
• Electron Transport Complex I

Topics

• Caulerpa (chemistry)
• Coloring Agents (chemistry, pharmacology)
• Electron Transport Complex I (antagonists & inhibitors)
• Female
• Humans
• Hypoxia-Inducible Factor 1 (drug effects)
• Indoles (chemistry, isolation & purification, pharmacology)
• Mitochondria (drug effects, metabolism)
• Molecular Structure
• Vascular Endothelial Growth Factor A (metabolism)