ADAPTIVE ALTERATIONS IN CELLULAR-METABOLISM WITH MALIGNANT TRANSFORMATION

Objective The authors studied the differences between glutamine and gl ucose utilization in normal fibroblasts and in fibrosarcoma cells to g ain insights into the metabolic changes that may ocour during malignan t transformation. Summary Background Data The process of malignant tra nsformation requires that cells acquire and use nutrients efficiently for energy, protein synthesis, and cell division. The two major source s of energy for cancer cells are glucose and glutamine. Glutamine is a lso essential for protein and DNA biosynthesis. We studied glucose and glutamine metabolism in normal and malignant fibroblasts, Methods Stu dies were done in normal rat kidney fibroblasts and in rat fibrosarcom a cells. We measured glutamine transport across the cell membrane, bre akdown of glutamine by the enzyme glutaminase (the first step in oxida tion), glutamine and glucose oxidation rates to CO2, rates of protein synthesis from glutamine, and glutamine-dependent growth rates. Result s Glutamine transport rates were increased more than sixfold in fibros arcomas compared to normal fibroblasts. In fibroblasts, glutamine tran sport was mediated by systems ASC and A. In malignant fibrosarcomas, o nly system ASC was identifiable, and its V-max was 15 times higher tha n that observed in fibroblasts. Despite an increase in transport, glut aminase activity was diminished and glutamine oxidation to CO2 was red uced in fibrosarcomas versus normal fibroblasts. In fibroblasts, gluta mine oxidation was 1.8 times higher than glucose oxidation. In contras t, glucose oxidation was 3.5 times greater than glutamine oxidation in fibrosarcomas. Protein synthesis from glutamine transported by fibros arcomas was threefold greater than that observed in normal fibroblasts . Despite marked increases in glutamine utilization and glucose oxidat ion in fibrosarcoma cells, growth rates were higher in the normal fibr oblasts. Conclusions The process of malignant transformation is associ ated with a marked increase in cellular glutamine transport, which is mediated by a single high-affinity, high-capacity plasma membrane carr ier protein. In normal fibroblasts, the transported glutamine is used primarily for energy production via oxidation of glutamine carbons to CO2. In fibrosarcomas, glutamine oxidation fails and glutamine is shun ted into protein synthesis; simultaneously, the malignant cell switche s to a glucose oxidizer. The increased glutamine transport and glucose oxidation in fibrosarcomas appears to be related to the malignant phe notype and not merely to an increase in cell growth rates.