Abstract Colon cancer cells possess remarkable metabolic adaptability, allowing them to survive under changing nutrient conditions. While this adaptive response is critical for tumor progression, the mechanistic underpinnings remain poorly characterized. Here, we investigate how colon cancer cells respond to glucose deprivation, with an emphasis on their shift from glycolysis to oxidative metabolism, ultimately leading to the emergence of a glucose-deprivation resistant (GDR) phenotype. To model metabolic stress, colon cancer cells were cultured in glucose-deprived environments. Metabolic shifts were assessed via Seahorse XF analysis to quantify glycolytic and oxidative phosphorylation (OXPHOS) activities. Metabolomic profiling by LC-MS was employed to identify changes in tricarboxylic acid (TCA) cycle intermediates and one-carbon metabolism-related metabolites (OCM). We found that glucose deprivation triggers extensive cell death and a dormant state in a subset of cells. However, a population of cells adapted by transitioning from a glycolysis-dependent metabolism to an OXPHOS-dominant profile. The lactate levels were transiently elevated during dormancy, and diminished significantly once cells resumed proliferation in the GDR state. Metabolomics analysis revealed heightened TCA cycle activity and enhanced mitochondrial respiration. Additionally, increased reactive oxygen species (ROS) levels observed during dormancy were mitigated in GDR cells through enhanced antioxidant systems. This adaptation conferred resistance to oxidative stress, as demonstrated by increased tolerance to hydrogen peroxide and sustained proliferation despite glycolysis inhibition by 2-deoxy-D-glucose. Concurrently, metabolites associated with OCM and supported redox homeostasis and biosynthetic processes were significantly upregulated, including methionine, folate, glutamine, pyridoxine, glycine, fumarate, cystine, and taurine. Gene expression analysis revealed significant upregulation of key enzymes involved in OCM pathways, highlighting its crucial role in ROS regulation of GDR cells under metabolic stress. These findings underscore the metabolic plasticity of colon cancer cells, where OXPHOS and OCM synergize to sustain proliferation under glucose scarcity, revealing potential therapeutic targets to overcome glucose deprivation resistance in tumors. Citation Format: Subha Ranjan Das, Bar Levi, Igor Koman, Elimelech Nesher. Oxidative Metabolism and One-Carbon Networks Enable Survival of Colon Cancer Cells in Glucose-Deprived Conditions abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P63.
Das et al. (Thu,) studied this question.