Galina 2013 Abstract MiP2013
|Galina A, Messeder DJM, Camacho-Pereira J, Pereira da Silva AP, Rodrigues-Ferreira C (2013) Effects of antitumor alkylating agent 3-bromopyruvate on energy transducing pathways in hepatoma HepG2, liver mitochondria and SERCA: Is there any role for mitochondrial hexokinase activity? Mitochondr Physiol Network 18.08.|
It was proposed that the alkylating agent 3-bromopyruvate (3-BrPA) could act as an antitumor agent in different cell lines of hepatocellular carcinoma mainly by targeting the mitochondrial hexokinase type 2 that is overexpressed in many tumor cells. Several revisions of drug therapy for cancer treatment have taken this as the main mechanism of action. Despite the potent negative effects of 3-BrPA on cell viability of the tumors, the analogue of pyruvate/lactate alkyl is oxidizing, as expected, other enzymes in energy transducing metabolism in tumor cells. However, little attention has been given to these side effects of 3-BrPA on tumor mitochondria, glycolysis and calcium pump SERCA. A dataset of high-resolution respirometry, analysis of flux, recovery of enzyme activities and metabolomics evaluated by our group in human hepatoma HepG2, isolated liver mitochondria and activities measured of calcium transport in sarcoplasmic reticulum vesicles mediated by SERCA, point to different metabolic targets with significant implications for the mechanism of cell death in tumor. Among the enzymes as targets we list the main ones: monocarboxylate transporter (MCT), glyceraldehyde dehydrogenase (GA3PDH); 3-phosphoglycerate kinase (3PGK); succinate dehydrogenase (SDH); pyruvate dehydrogenase (PDH); glutamate dehydrogenase (GDH); malate dehydrogenase (MDH) and SERCA 2a. Interestingly, mt-HK 1 and 2 are not significantly inhibited by 3-BrPA, but on the contrary contribute to depletion of the cytosolic ATP pool of the ATP-consuming path of glycolysis. Importantly, the mt-HK acts by modulating the rate of oxidative phosphorylation putting succinate dehydrogenase in a state of greater reactivity and inhibition by 3-BrPA. Given these observations we postulate that the mitochondrial hexokinase is not the primary molecular target of tumor cells but a potent depletory agent of cellular ATP and modulator of succinate dehydrogenase inhibition in mitochondrial supported respiration and inducer of permeability transition pore formation involved in cell death in tumor cells.
• O2k-Network Lab: BR Rio de Janeiro Galina A
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cancer Stress:Cell death, Permeability transition Organism: Rat Tissue;cell: Skeletal muscle, Nervous system, Liver, Other cell lines Preparation: Intact cells, Permeabilized cells, Isolated mitochondria, Enzyme Enzyme: Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Marker enzyme, TCA cycle and matrix dehydrogenases Regulation: Calcium, Flux control, mt-Membrane potential, Redox state, Threshold;excess capacity Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: N, S HRR: Oxygraph-2k
Laboratório de Bioenergética e Fisiologia Mitocondrial, Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Brazil. - Email: [email protected]