Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner

Abstract

Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.

Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

“…Importantly, tumors are not metabolically homogeneous and the glycolytic or oxidative phenotype can depend on nutrient availability and the microenvironment. For instance, Shiratori et al [23] demonstrated that the suppression of glycolysis in different cancer cells including pancreatic (Panc-1 cell line), induces a dramatic switch towards the OXPHOS profile. This switch is characterized by an increase in enzymes involved in TCA cycle and OXPHOS, as well as an increase in mitochondrial dynamics and mitochondrial membrane potential.…”

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

“…It has been suggested that common hexoses other than glucose, such as galactose and fructose, are also involved in the growth and metastasis of cancer cells. Galactose has been shown to induce OXPHOS-dependent metabolism and suppress the growth and metastasis of cancer cells [ 84 , 85 , 86 ]. On the other hand, fructose has been shown to promote liver metastasis in colon cancer and breast cancer [ 87 ].…”

Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose

“…Human platelets, a fresh source of viable mitochondria, have been described to rely on oxidative phosphorylation and reflect mitochondrial function of other, more metabolically active tissues [35][36][37][38]. Also cancer cells, long believed to rely solely on glycolysis, have now been described to upregulate their mitochondrial metabolism under certain conditions and rely on mitochondrial function for several cancerogenic processes [39,40]. Even though there are important differences between primary hepatocytes, HepG2 cells and human platelets, our data indicate that they show a relative comparable sensitivity towards drug-induced mitochondrial dysfunction, as indicated by the similar IC 50 values determined in this study.…”