ADAPTIVE REGULATION OF AMINO-ACID-TRANSPORT - IN NUTRIENT DEPRIVED HUMAN HEPATOMAS

BACKGROUND: Malignant cells require increased amounts of amino acids, in particular glutamine and leucine, to support DNA and protein biosyn thesis. Although plasma concentrations in the center of solid tumors c an be much lower than normal circulating levels, it is still unknown h ow tumor cells can survive despite low amino acid levels. We examined the effects of glutamine or leucine deprivation on cell growth and, am ino acid transport activity in two human hepatoma cell lines, SK-Hep a nd HepG2. METHODS: We studied the transport of glutamine, leucine, ala nine, and arginine. The carrier-mediated uptake of H-3-amino acids was determined in cells cultured in normal and amino acid-deprived media. RESULTS: The growth of both cell lines was dependent on the concentra tion of glutamine and leucine. In SK-Hep, there was a significant incr ease in initial rate glutamine transport activity in the glutamine-der ived group, attributable to an increase in transporter affinity (Km; 0 .6 mmol/L [control], 385+/-43 mu mol/L; 0.1 mmol/L, 221+/-11 mu mol/L; P<0.01). At low glutamine concentration, the saturable Na+-independen t uptake of leucine and arginine,as well as the Na+-dependent uptake o f alanine increased significantly in both SK-Hep and HepG2. Similarly, in leucine-deprived SK-Hep cells, leucine uptake increased twofold, b ut the change was attributable to an enhanced transporter capacity (Vm ax; 0.2 mmol/L [control], 38,900+/-700; 0.0 mmol/L, 75,900+/-4,900 pmo l/mg protein per minute; P<0.001). CONCLUSIONS: Adaptive increases in initial rate amino acid transport activities were elicited by glutamin e and leucine deprivation in these two human hepatoma cell lines. Decr eased extracellular amino acid levels encountered by tumors in vivo ma y elicit similar adaptive responses that contribute to the maintenance of cytoplasmic levels of amino acids essential for growth.