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-N-acetylhexosamines (
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 feedback regulation of
glutamine:
fructose-6-P amidotransferase (EC 2.6.1.16), which can be circumvented by
glucosamine. Using 31P nuclear magnetic resonance analysis of extracts and perfused cells, we have identified
UDP-
N-acetylglucosamine and
UDP-N-
acetylgalactosamine as the primary metabolites in the DPDE spectral region of SCLC-V N-417 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
N-acetylglucosamine 6-phosphate and
UDP-
N-acetylglucosamine 1-phosphate is also observed, indicating
UTP limitation. Subsequent
uridine addition results in depletion of the intermediates 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.