title: Glucose metabolism is inhibited by caspases upon the induction of apoptosis.
abstract: Rapidly proliferating cells, such as cancer cells, have adopted aerobic glycolysis rather than oxidative phosphorylation to supply their energy demand; this phenomenon is known as 'the Warburg effect'. It is now widely accepted that during apoptosis the loss of energy production, orchestrated by caspases, contributes to the dismantling of the dying cell. However, how this loss of energy production occurs is still only partially known. In the present work, we established that during apoptosis the level of cellular ATP decreased in a caspase-dependent manner. We demonstrated that this decrease in ATP content was independent of any caspase modification of glucose uptake, ATP consumption or reactive oxygen species production but was dependent on a caspase-dependent inhibition of glycolysis. We found that the activity of the two glycolysis-limiting enzymes, phosphofructokinase and pyruvate kinase, were affected by caspases, whereas the activity of phosphoglycerate kinase was not, suggesting specificity of the effect. Finally, using a metabolomic analysis, we observed that caspases led to a decrease in several key metabolites, including phosphoserine, which is a major regulator of pyruvate kinase muscle isozyme activity. Thus, we have established that during apoptosis, caspases can shut down the main energy production pathway in cancer cells, leading to the impairment in the activity of the two enzymes controlling limiting steps of glycolysis.
authors.affiliation: 1] Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 'contrôle métabolique des morts cellulaires', Nice, France [2] Faculté de Médecine, Université de Nice-Sophia-Antipolis, Nice, France.
authors.forename: L A
authors.initials: LA
authors.lastname: Pradelli
authors.affiliation: 1] Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 'contrôle métabolique des morts cellulaires', Nice, France [2] Faculté de Médecine, Université de Nice-Sophia-Antipolis, Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Villa
authors.affiliation: 1] Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 'contrôle métabolique des morts cellulaires', Nice, France [2] Faculté de Médecine, Université de Nice-Sophia-Antipolis, Nice, France [3] Département d'Anesthésie Réanimation, Centre Hospitalier Universitaire de Nice, Nice, France.
authors.forename: B
authors.initials: B
authors.lastname: Zunino
authors.affiliation: 1] Faculté de Médecine, Université de Nice-Sophia-Antipolis, Nice, France [2] Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 'mort cellulaire, différenciation et cancer', Nice, France.
authors.forename: S
authors.initials: S
authors.lastname: Marchetti
authors.affiliation: 1] Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 'contrôle métabolique des morts cellulaires', Nice, France [2] Faculté de Médecine, Université de Nice-Sophia-Antipolis, Nice, France [3] Département d'Anesthésie Réanimation, Centre Hospitalier Universitaire de Nice, Nice, France.
authors.forename: J-E
authors.initials: JE
authors.lastname: Ricci
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000737:chemistry / Q000378:metabolism*; D003847:Deoxyglucose / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D010732:Phosphofructokinase-1 / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012427:Rutamycin / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D011804:Quinolines; D017382:Reactive Oxygen Species; C468548:quinoline-val-asp(OMe)-CH2-OPH; D012427:Rutamycin; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D010732:Phosphofructokinase-1; D011770:Pyruvate Kinase; D020169:Caspases; D019311:Staurosporine; D005947:Glucose