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

Christian Frezza, Liang Zheng, Daniel A. Tennant, Dmitri B Papkovsky, Barbara A Hedley, Gabriela Kalna, David Watson, Eyal Gottlieb

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

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.
LanguageEnglish
Article numbere24411
Number of pages10
JournalPLoS One
Volume6
Issue number9
DOIs
Publication statusPublished - 2 Sep 2011

Fingerprint

metabolomics
cell viability
hypoxia
Cell Survival
Cells
Autophagy
Oxygen
Tumors
Cell Hypoxia
autophagy
Metabolomics
Neoplasms
cells
Adenosine Triphosphate
oxygen
anaerobic conditions
HCT116 Cells
Metabolome
Oxidative Phosphorylation
Liquid chromatography

Keywords

  • cytochrome-oxidase
  • homeostasis
  • respiration
  • erythrocytes
  • cancer
  • autophagy
  • HIF-1
  • acyl-carnitine
  • inducible factor-1
  • mitochondrial oxygen-consumption

Cite this

Frezza, C., Zheng, L., Tennant, D. A., Papkovsky, D. B., Hedley, B. A., Kalna, G., ... Gottlieb, E. (2011). Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS One, 6(9), [e24411]. https://doi.org/10.1371/journal.pone.0024411
Frezza, Christian ; Zheng, Liang ; Tennant, Daniel A. ; Papkovsky, Dmitri B ; Hedley, Barbara A ; Kalna, Gabriela ; Watson, David ; Gottlieb, Eyal. / Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. In: PLoS One. 2011 ; Vol. 6, No. 9.
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Frezza, C, Zheng, L, Tennant, DA, Papkovsky, DB, Hedley, BA, Kalna, G, Watson, D & Gottlieb, E 2011, 'Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival' PLoS One, vol. 6, no. 9, e24411. https://doi.org/10.1371/journal.pone.0024411

Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. / Frezza, Christian; Zheng, Liang; Tennant, Daniel A.; Papkovsky, Dmitri B; Hedley, Barbara A; Kalna, Gabriela; Watson, David; Gottlieb, Eyal.

In: PLoS One, Vol. 6, No. 9, e24411, 02.09.2011.

Research output: Contribution to journalArticle

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AU - Frezza, Christian

AU - Zheng, Liang

AU - Tennant, Daniel A.

AU - Papkovsky, Dmitri B

AU - Hedley, Barbara A

AU - Kalna, Gabriela

AU - Watson, David

AU - Gottlieb, Eyal

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Frezza C, Zheng L, Tennant DA, Papkovsky DB, Hedley BA, Kalna G et al. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PLoS One. 2011 Sep 2;6(9). e24411. https://doi.org/10.1371/journal.pone.0024411