Abstract
The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate 13C6-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. 13C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network.
Highlights
CANCER CELLS IN A LIMITING NUTRITIONAL MICROENVIRONMENTCancers consist of a plethora of cells with different metabolic phenotypes in a microenvironment of fluctuating nutrient availability, along with other changes in physico-chemical variables supporting or jeopardizing cell survival (Figure 1)
Considering that numerous views and reviews have been written on cancer metabolism [3,4,5,6], each highlighting a different angle of the biochemistry and molecular biology of uncontrollable growth of cancer cells—which new perspective will be taken here? Our basic understanding of cancer metabolism has been shaped by studying cancer cells cultured mainly in saturating nutrient conditions, i.e. those resembling a well-fed, even diabetic physiology
MCF-7 cells express the glucose transporters GLUT1 and GLUT3, whose levels are increased in hypoglycemic conditions and are rate limiting for glycolysis [22]
Summary
Cancers consist of a plethora of cells with different metabolic phenotypes in a microenvironment of fluctuating nutrient availability, along with other changes in physico-chemical variables supporting or jeopardizing cell survival (Figure 1) This cellular heterogeneity poses a challenge for metabolic imaging, diagnosis and chemo-therapeutic targeting in the clinic. Metabolite detection by gas chromatography with mass spectrometry (GC-MS) allows to identify and semi-quantify a number of metabolites with regards to 1) their cellular levels; 2) their 13C-enrichment, which is a product of the metabolite pool and metabolic flux; and 3) 13C-isotope profiles, which provide information on different metabolic roads taken by 13C-glucose-derived metabolites [18,19,20,21] These analyses attest pyruvate a key role in metabolic plasticity
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