title: Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism: A review.
abstract: 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.
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada. Electronic address: Jerry.Vriend@med.umanitoba.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vriend
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015687:Cell Hypoxia; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000502:physiology; D010100:Oxygen / Q000032:analysis*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000502:physiology*
chemical_list: D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D008550:Melatonin; D010100:Oxygen
keywords: Hypoxia; Hypoxia response element; Melatonin; Proteasome; Ubiquitin ligase; Warburg effect; von Hippel–Lindau tumor suppressor