On the mechanism of the glucose-induced ATP catabolism in ascites tumour cells and its reversal by pyruvate.
Addition of glucose to Ehrlich-Landschütz ascites tumour cells preincubated for 30-60 min in phosphate-buffered Krebs-Ringer salt solution ("starved cells") resulted within 1-2 min in an approx. 90% decline of their ATP content and a massive accumulation of fructose 1,6-bisphosphate. These alterations, which took place under both aerobic and anaerobic conditions, were followed by a gradual spontaneous recovery with restoration of normal ATP and fructose 1,6-bisphosphate values. The transient derangement of the energy metabolism after glucose addition to starved ascites tumour cells by preventable by simultaneous addition of pyruvate or 2-oxobutyrate, or by preincubating the cells in the presence of glucose. The protective effect of pyruvate was duplicated by addition of phenazine methosulphate or NAD+ to the incubation medium. The data seem to warrant the conclusion that the glucose-induced ATP depletion is determined by a blockade of glycolysis at the stage of glyceraldehyde phosphate dehydrogenase caused by the failure of the cells to oxidize the NADH produced in the same reaction. The continued unrestrained action of 6-phosphofructokinase results in accumulation of fructose 1,6-bisphosphate, which constitutes a trap for the high-energy phosphate bonds of ATP. The primary metabolic disturbance appears to consist of a transient inhibition of pyruvate kinase with the resultant inability of the cells to maintain an unimpaired supply of pyruvate, as required for the lactate dehydrogenase-mediated oxidation of NADH. The regulatory mechanism underlying this phenomenon is discussed.
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000693:Anaerobiosis; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D002478:Cells, Cultured; D005635:Fructosediphosphates / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D051379:Mice; D009243:NAD / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*
D005635:Fructosediphosphates; D011773:Pyruvates; D009243:NAD; D000968:Antimycin A; D000255:Adenosine Triphosphate; D005947:Glucose