Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.
Affiliation
Systems Biology Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.Issue Date
2011-03-01MeSH
Adenosine TriphosphateApoptosis
Caspase 3
Cell Line
Cytochromes c
Energy Metabolism
Glucose
Hela Cells
Humans
Membrane Potential, Mitochondrial
Membrane Potentials
Mitochondria
Models, Theoretical
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Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release. 2011, 7:470 Mol. Syst. Biol.Journal
Molecular systems biologyDOI
10.1038/msb.2011.2PubMed ID
21364572Additional Links
http://www.ncbi.nlm.nih.gov/pubmed/21364572Abstract
Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨ(m) from -142 to -88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨ(m). However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell's glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.Item Type
ArticleLanguage
enISSN
1744-4292ae974a485f413a2113503eed53cd6c53
10.1038/msb.2011.2
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