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Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival.

Hypoxia is one of the features of poorly vascularised areas of solid tumours but cancer cells can survive in these areas despite the low oxygen tension. The adaptation to hypoxia requires both biochemical and genetic responses that culminate in a metabolic rearrangement to counter-balance the decrea... Full description

Journal Title: PloS one 2011, Vol.6(9), p.e24411
Main Author: Frezza, Christian
Other Authors: Zheng, Liang , Tennant, Daniel A , Papkovsky, Dmitri B , Hedley, Barbara A , Kalna, Gabriela , Watson, David G , Gottlieb, Eyal
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0024411
Link: http://search.proquest.com/docview/889451362/?pq-origsite=primo
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recordid: proquest889451362
title: Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival.
format: Article
creator:
  • Frezza, Christian
  • Zheng, Liang
  • Tennant, Daniel A
  • Papkovsky, Dmitri B
  • Hedley, Barbara A
  • Kalna, Gabriela
  • Watson, David G
  • Gottlieb, Eyal
subjects:
  • Anaerobiosis–Metabolism
  • Cell Hypoxia–Metabolism
  • Cell Survival–Metabolism
  • Glycolysis–Metabolism
  • Hct116 Cells–Metabolism
  • Humans–Metabolism
  • Metabolomics–Metabolism
  • Microscopy–Metabolism
  • Mitochondria–Metabolism
  • Phenotype–Metabolism
ispartof: PloS one, 2011, Vol.6(9), p.e24411
description: Hypoxia is one of the features of poorly vascularised areas of solid tumours but cancer cells can survive in these areas despite the low oxygen tension. The adaptation to hypoxia requires both biochemical and genetic responses that culminate in a metabolic rearrangement to counter-balance the decrease in energy supply from mitochondrial respiration. The understanding of metabolic adaptations under hypoxia could reveal novel pathways that, if targeted, would lead to specific death of hypoxic regions. In this study, we developed biochemical and metabolomic analyses to assess the effects of hypoxia on cellular metabolism of HCT116 cancer cell line. We utilized an oxygen fluorescent probe in anaerobic cuvettes to study oxygen consumption rates under hypoxic conditions without the need to re-oxygenate the cells and demonstrated that hypoxic cells can maintain active, though diminished, oxidative phosphorylation even at 1% oxygen. These results were further supported by in situ microscopy analysis of mitochondrial NADH oxidation under hypoxia. We then used metabolomic methodologies, utilizing liquid chromatography-mass spectrometry (LC-MS), to determine the metabolic profile of hypoxic cells. This approach revealed the importance of synchronized and regulated catabolism as a mechanism of adaptation to bioenergetic stress. We then confirmed the presence of autophagy under hypoxic conditions and demonstrated that the inhibition of this catabolic process dramatically reduced the ATP levels in hypoxic cells and stimulated hypoxia-induced cell death. These results suggest that under hypoxia, autophagy is required to support ATP production, in addition to glycolysis, and that the inhibition of autophagy might be used to selectively target hypoxic regions of tumours, the most notoriously resistant areas of solid tumours.
language: eng
source:
identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0024411
fulltext: fulltext
issn:
  • 19326203
  • 1932-6203
url: Link


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titleMetabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival.
creatorFrezza, Christian ; Zheng, Liang ; Tennant, Daniel A ; Papkovsky, Dmitri B ; Hedley, Barbara A ; Kalna, Gabriela ; Watson, David G ; Gottlieb, Eyal
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subjectAnaerobiosis–Metabolism ; Cell Hypoxia–Metabolism ; Cell Survival–Metabolism ; Glycolysis–Metabolism ; Hct116 Cells–Metabolism ; Humans–Metabolism ; Metabolomics–Metabolism ; Microscopy–Metabolism ; Mitochondria–Metabolism ; Phenotype–Metabolism
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descriptionHypoxia is one of the features of poorly vascularised areas of solid tumours but cancer cells can survive in these areas despite the low oxygen tension. The adaptation to hypoxia requires both biochemical and genetic responses that culminate in a metabolic rearrangement to counter-balance the decrease in energy supply from mitochondrial respiration. The understanding of metabolic adaptations under hypoxia could reveal novel pathways that, if targeted, would lead to specific death of hypoxic regions. In this study, we developed biochemical and metabolomic analyses to assess the effects of hypoxia on cellular metabolism of HCT116 cancer cell line. We utilized an oxygen fluorescent probe in anaerobic cuvettes to study oxygen consumption rates under hypoxic conditions without the need to re-oxygenate the cells and demonstrated that hypoxic cells can maintain active, though diminished, oxidative phosphorylation even at 1% oxygen. These results were further supported by in situ microscopy analysis of mitochondrial NADH oxidation under hypoxia. We then used metabolomic methodologies, utilizing liquid chromatography-mass spectrometry (LC-MS), to determine the metabolic profile of hypoxic cells. This approach revealed the importance of synchronized and regulated catabolism as a mechanism of adaptation to bioenergetic stress. We then confirmed the presence of autophagy under hypoxic conditions and demonstrated that the inhibition of this catabolic process dramatically reduced the ATP levels in hypoxic cells and stimulated hypoxia-induced cell death. These results suggest that under hypoxia, autophagy is required to support ATP production, in addition to glycolysis, and that the inhibition of autophagy might be used to selectively target hypoxic regions of tumours, the most notoriously resistant areas of solid tumours.
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