The Role of Glycolysis in the Growth of Tumor Cells

Otto Warburg demonstrated the high rate of aerobic glycolysisr of tumors in titro and postulated this as a unique requirement for neoplastic growth. (For a recent review see Aisenberg (I).) There is evidence that this metabolic anomaly is not due to a fundamental difference between normal and tumor cells but merely reflects their particular growth rates. For example, some years ago O’Connor (2,3) demonstrated a linear correlation between glycolysis of chick embryo midbrain and mitotic index (which is a good index of growth in this tissue). More recently the Morris hepatoma, a very slowly growing tumor, was found to have low glycolytic activity (4, 5). It is well established that cells derived from normal tissue that have adapted to an environment in vitro and grow rapidly have a high glycolytic rate (6). The question has not been satisfactorily answered as to whether the glycolysis of rapidly dividing cells is essential to their growth. In this report we will deal only with the more particular question, “Do tumor cells require glycolysis to grow” ? Our general approach to this question was indicated in a previous report (7). It was shown there that oxamic acid, an inhibitor of lactic dehydrogenase competitive with pyruvate (8), will inhibit the glycolysis but not the respiration of resting Ehrlich ascites tumor cells. It was also shown that pyruvate accumulated under anaerobic conditions in the presence of oxamate and eventually reversed the inhibition of glycolysis in these ascites cells. This indicated that the site of action of oxamate in this case was probably at lactic dehydrogenase. To test the requirement of glycolysis for growth, a fast growing tumor cell in vitro, HeLa S3, was used. Oxamate inhibited growth, glycolysis, and glucose uptake of these cells (9). All of these effects of oxamate were reversed when pyruvate was also present in the medium, indicating that the site of action of oxamate for these inhibitions in HeLa cells was at lactic dehydrogenase. Two main objections to this conclusion remained to be overcome. First, the previous experiments with HeLa cells were done with small inocula which were allowed to grow about B-fold. Thus, in those experiments the rate of glycolysis was not deter-