Melatonin and the von Hippel–Lindau/HIF-1 oxygen sensing mechanism: A review

There are numerous reports that melatonin inhibits the hypoxia-inducible factor, HIF-1α, and the HIF-1α-inducible gene, VEGF, both in vivo and in vitro. Through the inhibition of the HIF-1-VEGF pathway, melatonin reduces hypoxia-induced angiogenesis. Herein we discuss the interaction of melatonin with HIF-1α and HIF-1α-inducible genes in terms of what is currently known concerning the HIF-1α hypoxia response element (HIF-1α-HRE) pathway. The von Hippel–Lindau protein (VHL), also known as the VHL tumor suppressor, functions as part of a ubiquitin ligase complex which recognizes HIF-1α as a substrate. As such, VHL is part of the oxygen sensing mechanism of the cell. Under conditions of hypoxia, HIF-1α stimulates the transcription of numerous HIF-1α-induced genes, including EPO, VEGF, and PFKFB3; the latter is an enzyme which regulates glycolysis. Data from several studies show that ROS generated in mitochondria under conditions of hypoxia stimulate HIF-1α. Since melatonin acts as an antioxidant and reduces ROS, these data suggest that the antioxidant action of melatonin could account for reduced HIF-1, less VEGF, and reduced glycolysis in cancer cells (Warburg effect). A direct or indirect inhibitory action (via the reduction in ROS) of melatonin on proteasome activity would account for much of the published data.