The Caulerpa pigment caulerpin inhibits HIF-1 activation and mitochondrial respiration.
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.
Liu
Yang
Y
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.
Morgan
J Brian
JB
Coothankandaswamy
Veena
V
Liu
Rui
R
Jekabsons
Mika B
MB
Mahdi
Fakhri
F
Nagle
Dale G
DG
Zhou
Yu-Dong
YD
D046068:Caulerpa / Q000737:chemistry*; D004396:Coloring Agents / Q000737:chemistry / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects*; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D004396:Coloring Agents; D051793:Hypoxia-Inducible Factor 1; D007211:Indoles; D042461:Vascular Endothelial Growth Factor A; C000392:caulerpin; D042967:Electron Transport Complex I