Conversion of Hyperpolarized [1-¹³ C]Pyruvate in Breast Cancer Cells Depends on Their Malignancy, Metabolic Program and Nutrient Microenvironment

Hyperpolarized magnetic resonance spectroscopy (MRS) is a technology for characterizing tumors in vivo based on their metabolic activities. The conversion rates (k_pl) of hyperpolarized [1-¹³ C]pyruvate to [1-¹³ C]lactate depend on monocarboxylate transporters (MCT) and lactate dehy-drogenase (LDH); these are also indicators of tumor malignancy. An unresolved issue is how glucose and glutamine availability in the tumor microenvironment affects metabolic characteristics of the cancer and how this relates to k_pl-values. Two breast cancer cells of different malignancy (MCF-7, MDA-MB-231) were cultured in media containing defined combinations of low glucose (1 mM; 2.5 mM) and glutamine (0.1 mM; 1 mM) and analyzed for pyruvate uptake, intracellular metabolite levels, LDH and pyruvate kinase activities, and¹³ C₆-glucose-derived metabolomics. The results show variability of k_pl with the different glucose/glutamine conditions, congruent with glycolytic activity, but not with LDH activity or the Warburg effect; this suggests metabolic compartmentation. Remarkably, k_pl-values were almost two-fold higher in MCF-7 than in the more malignant MDA-MB-231 cells, the latter showing a higher flux of¹³ C-glucose-derived pyruvate to the TCA-cycle metabolites¹³ C₂-citrate and¹³ C₃-malate, i.e., pyruvate decarboxylation and carboxylation, respec-tively. Thus, MRS with hyperpolarized [1-¹³ C-pyruvate] is sensitive to both the metabolic program and the nutritional state of cancer cells.