Aerobic glycolysis during lymphocyte proliferation

GLYCOLYSIS, for most mammalian cells, is only a prelude to the complete respiratory oxidation of glucose. Lactate production is usually barely, if at all, detectable in aerobic conditions¹. Consequently, when Warburg^2,3 observed that various tumours showed active aerobic glycolysis, he postulated that defective tumour cell respiration was the reason and was, moreover, the basic difference between normal and cancer cells. Although aerobic glycolysis by tumour tissue has been confirmed many times, defective respiration in cancer cells has not been established⁴. The failure to uncover a respiratory defect in cancer cells has led to other explanations. It has been suggested, for example, that aerobic glycolysis is linked to cell growth rather than to malignancy⁵, and for several hepatomas a correlation could be made between the amount of lactate produced and the cell doubling time^6,7. It follows that if aerobic glycolysis is related to cell growth, it might be possible as much in normal as malignant cells. There is some evidence for this. Aerobic glycolysis has been noted in proliferating fibroblasts during the period of maximum increase in cell numbers^8,9. Human lymphocytes have shown an increase in respiration and also produced lactate when stimulated by the mitogen phytohaemagglutinin^10,11. In chick embryo and skeletal muscle fibroblasts^12,13, glycolysis increased during log phase growth, but several factors seemed to influence lactate production. Medium composition, aggregation state of cells, culture pH and cell density were all considered more important in determining glycolytic activity than growth rate. It should be noted, however, that these factors are also important to the proliferative rate of these cells. We believe that the important question is not whether culture conditions can influence lactate production, but rather whether glycolysis is linked to cell division. So far no systematic study of the relationship of the appearance of aerobic glycolysis to cell proliferation or the phases of the cell cycle has been reported. This report presents evidence in normal lymphocytes that aerobic glycolysis not only is associated with cellular proliferation, but more specifically is temporally related to DNA synthesis.