Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.

Hdl Handle:
http://hdl.handle.net/10147/135438
Title:
Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.
Authors:
Huber, Heinrich J; Dussmann, Heiko; Kilbride, Seán M; Rehm, Markus; Prehn, Jochen H M
Affiliation:
Systems Biology Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Citation:
Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release. 2011, 7:470 Mol. Syst. Biol.
Journal:
Molecular systems biology
Issue Date:
1-Mar-2011
URI:
http://hdl.handle.net/10147/135438
DOI:
10.1038/msb.2011.2
PubMed ID:
21364572
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed/21364572
Abstract:
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:
Article
Language:
en
MeSH:
Adenosine Triphosphate; Apoptosis; Caspase 3; Cell Line; Cytochromes c; Energy Metabolism; Glucose; Hela Cells; Humans; Membrane Potential, Mitochondrial; Membrane Potentials; Mitochondria; Models, Theoretical
ISSN:
1744-4292

Full metadata record

DC FieldValue Language
dc.contributor.authorHuber, Heinrich Jen
dc.contributor.authorDussmann, Heikoen
dc.contributor.authorKilbride, Seán Men
dc.contributor.authorRehm, Markusen
dc.contributor.authorPrehn, Jochen H Men
dc.date.accessioned2011-07-06T09:29:50Z-
dc.date.available2011-07-06T09:29:50Z-
dc.date.issued2011-03-01-
dc.identifier.citationGlucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release. 2011, 7:470 Mol. Syst. Biol.en
dc.identifier.issn1744-4292-
dc.identifier.pmid21364572-
dc.identifier.doi10.1038/msb.2011.2-
dc.identifier.urihttp://hdl.handle.net/10147/135438-
dc.description.abstractMany 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.-
dc.language.isoenen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/21364572en
dc.subject.meshAdenosine Triphosphate-
dc.subject.meshApoptosis-
dc.subject.meshCaspase 3-
dc.subject.meshCell Line-
dc.subject.meshCytochromes c-
dc.subject.meshEnergy Metabolism-
dc.subject.meshGlucose-
dc.subject.meshHela Cells-
dc.subject.meshHumans-
dc.subject.meshMembrane Potential, Mitochondrial-
dc.subject.meshMembrane Potentials-
dc.subject.meshMitochondria-
dc.subject.meshModels, Theoretical-
dc.titleGlucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release.en
dc.typeArticleen
dc.contributor.departmentSystems Biology Group, Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.en
dc.identifier.journalMolecular systems biologyen

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