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Decoupled glucose- and glutamine-dependent orthogonal metabolic states independently sustain cancer cell survival

ABSTRACT: Cancer metabolism is often framed as dependence on cooperative glucose-glutamine fuels; however, whether distinct nutrients enforce discrete metabolic states remains unclear. Glucose utilization is often interpreted under Warburg physiology, involving accelerated glycolysis and clockwise TCA rotation to generate reducing equivalents; yet, emerging evidence suggests that glutamine, under certain conditions, can drive anaplerotic pathways independent of glycolysis, involving a counterclockwise TCA linked to massive lipid biosynthesis. Here, we sought to define how glucose and glutamine independently govern adaptive metabolic states, rather than functioning as cooperative co-fuels, in MDA-MB-231 breast cancer cells. Briefly, cells were cultured under four defined nutrient conditions—full (+Glc,+Gln), deficient (−Glc,−Gln), glucose-only, and glutamine-only—and applied transcriptomic, metabolomic, and lipidomic analyses to resolve nutrient-enforced transcriptional and metabolic states.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317435 | GEO | 2026/01/24

REPOSITORIES: GEO

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Project description:Cell proliferation is achieved by numerous enzyme reactions. Temperature governs the activity of each enzyme, which overall determines the optimal growth temperature. Synthesizing useful chemicals and fuels utilizes only part of the metabolic pathways, especially the central metabolic pathways such as glycolysis and TCA cycle to metabolize glucose. However, the optimal temperature for the activity of the central metabolic pathways is inconclusive whether it is correlated with the optimal temperature for cell proliferation. Here, we found that Corynebacterium glutamicum wild type increased the metabolic activity to consume glucose under anaerobic (oxygen deprived) conditions at 42.5ºC, in which the cell hardly grows under aerobic conditions. Glucose consumption rate was increased by 24% at 42.5ºC compared to that at the optimal growth temperature of 30.0ºC. Transcriptional analysis showed that gapX gene encoding glycelaldehydre-3-phosphate dehydrogenase, glucokinase gene, and a gene involved in glucose uptake were upregulated at 42.5ºC. Production of fermentative lactate was increased by 69% than that at 30.0ºC, whereas succinate production was decreased by 13%. In addition to several glycolytic enzymes, the activity of pyruvate kinase was increased with increasing the temperature, whereas the activity of phosphoenolpyruvate carboxylase in anapleotic pathway leading to succinate synthesis was decreased. However, a metabolically engineered succinate over-producing strain, in which lactate production was shut off and pyruvate carboxylase encoding gene in another anapleotic pathway was overexpressed, produced 34% higher succinate at 42.5ºC than that at 30.0ºC with increased glucose consumption. This study provides the evidence that the optimal reaction temperature for production of fermentative products can be set beyond upper limit of growth temperature in C. glutamicum, and hence it could be applicable for producing various chemicals and fuels in C. glutamicum under anaerobic conditions and non-growing cell reactions in other microorganisms.

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Decoupled glucose- and glutamine-dependent orthogonal metabolic states independently sustain cancer cell survival

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