title: Alterations in cellular energy metabolism associated with the antiproliferative effects of the ATM inhibitor KU-55933 and with metformin.
abstract: KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM), an important tumor suppressor gene with key roles in DNA repair. Unexpectedly for an inhibitor of a tumor suppressor gene, KU-55933 reduces proliferation. In view of prior preliminary evidence suggesting defective mitochondrial function in cells of patients with Ataxia Telangiectasia (AT), we examined energy metabolism of cells treated with KU-55933. The compound increased AMPK activation, glucose uptake and lactate production while reducing mitochondrial membrane potential and coupled respiration. The stimulation of glycolysis by KU-55933 did not fully compensate for the reduction in mitochondrial functions, leading to decreased cellular ATP levels and energy stress. These actions are similar to those previously described for the biguanide metformin, a partial inhibitor of respiratory complex I. Both compounds decreased mitochondrial coupled respiration and reduced cellular concentrations of fumarate, malate, citrate, and alpha-ketogluterate. Succinate levels were increased by KU-55933 levels and decreased by metformin, indicating that the effects of ATM inhibition and metformin are not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metformin perturb the TCA cycle as well as oxidative phosphorylation.
authors.affiliation: Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Mahvash
authors.initials: M
authors.lastname: Zakikhani
authors.forename: Miguel
authors.initials: M
authors.lastname: Bazile
authors.forename: Sina
authors.initials: S
authors.lastname: Hashemi
authors.forename: Shiva
authors.initials: S
authors.lastname: Javeshghani
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.forename: Julie
authors.initials: J
authors.lastname: St Pierre
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019343:Citric Acid / Q000737:chemistry; D002952:Citric Acid Cycle; D004268:DNA-Binding Proteins / Q000378:metabolism; D005650:Fumarates / Q000737:chemistry; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007656:Ketoglutaric Acids / Q000737:chemistry; D008293:Malates / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial; D008687:Metformin / Q000378:metabolism* / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology*; D010101:Oxygen Consumption; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D019802:Succinic Acid / Q000737:chemistry; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005650:Fumarates; D007004:Hypoglycemic Agents; D007656:Ketoglutaric Acids; D008293:Malates; D009025:Morpholines; D011753:Pyrones; D025521:Tumor Suppressor Proteins; D019343:Citric Acid; C030298:malic acid; D008687:Metformin; D019802:Succinic Acid; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases