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

A review

Jerry Vriend, Russel J Reiter

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)176-183
Number of pages8
JournalBiochimica et Biophysica Acta - Reviews on Cancer
Volume1865
Issue number2
DOIs
StatePublished - Apr 1 2016

Fingerprint

Melatonin
Oxygen
Vascular Endothelial Growth Factor A
Glycolysis
Von Hippel-Lindau Tumor Suppressor Protein
Antioxidants
Genes
Hypoxia-Inducible Factor 1
Response Elements
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
Mitochondria
Proteins
Hypoxia
Enzymes
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism : A review. / Vriend, Jerry; Reiter, Russel J.

In: Biochimica et Biophysica Acta - Reviews on Cancer, Vol. 1865, No. 2, 01.04.2016, p. 176-183.

Research output: Contribution to journalArticle

@article{7f974a4c12034f7d84331ac2402afb95,
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.",
keywords = "Hypoxia, Hypoxia response element, Melatonin, Proteasome, Ubiquitin ligase, Von Hippel-Lindau tumor suppressor, Warburg effect",
author = "Jerry Vriend and Reiter, {Russel J}",
year = "2016",
month = "4",
day = "1",
doi = "10.1016/j.bbcan.2016.02.004",
language = "English (US)",
volume = "1865",
pages = "176--183",
journal = "Biochimica et Biophysica Acta - Reviews on Cancer",
issn = "0304-419X",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism

T2 - A review

AU - Vriend, Jerry

AU - Reiter, Russel J

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

KW - Hypoxia

KW - Hypoxia response element

KW - Melatonin

KW - Proteasome

KW - Ubiquitin ligase

KW - Von Hippel-Lindau tumor suppressor

KW - Warburg effect

UR - http://www.scopus.com/inward/record.url?scp=84959087721&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959087721&partnerID=8YFLogxK

U2 - 10.1016/j.bbcan.2016.02.004

DO - 10.1016/j.bbcan.2016.02.004

M3 - Article

VL - 1865

SP - 176

EP - 183

JO - Biochimica et Biophysica Acta - Reviews on Cancer

JF - Biochimica et Biophysica Acta - Reviews on Cancer

SN - 0304-419X

IS - 2

ER -