UDP-jY-Acetylhexosamine Modulation by Glucosamine and Uridine in NCI N-417 Variant Small Cell Lung Cancer Cells: 31P Nuclear Magnetic Resonance Results1

Small cell lung cancer (SCLC) occurs as two neuroendocrine subtypes, SCLC-C (classic) and SCLC-V (variant). One reported difference is elevated levels of diphosphodiesters (DPDE) in the more differentiated SCLC-C subtype. DPDE have been identified as primarily UDP-JVacetylhexosamines (UDP-NAH) in a variety of tumors, and changes in DPDE levels have been observed during experiments designed to induce cell differentiation. UDP-NAH synthesis is controlled by negative feed back regulation of glutamine:fructose-6-P amidotransferase (EC 2.6.1.16), which can be circumvented by glucosamine. Using "I* nuclear magnetic resonance analysis of extracts and perfused cells, we have identified UDP-/V-acetylglucosamine and UDP-A/-acetylgalactosamine as the primary metabolites in the DPDE spectra) region of SCLC-V N417 cells. Glucosamine addition causes a rapid increase in UDP-NAH levels. At glucosamine: glucose ratios of 1:1 and 10:1 formation of the UDP-NAH intermediates /V-acetylglucosamine 6-phosphate and I '1)1'/V-acetylglucosamine 1-phosphate is also observed, indicating UTP lim itation. Subsequent uridine addition results in depletion of the interme diates and increased UDP-NAH formation. Moreover, N-417 cells retain the capacity to rapidly convert uridine to UTP despite low ATP and phosphocreatine levels. This expansion of the uridine pool may represent an additional metabolic reserve not yet addressed in the design of therapy options.