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

Jerry Vriend, Russel J. Reiter

Research output: Contribution to journalReview articlepeer-review

54 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)176-183
Number of pages8
JournalBiochimica et Biophysica Acta - Reviews on Cancer
Issue number2
StatePublished - Apr 1 2016


  • Hypoxia
  • Hypoxia response element
  • Melatonin
  • Proteasome
  • Ubiquitin ligase
  • Von Hippel-Lindau tumor suppressor
  • Warburg effect

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research


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