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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.

SUBMITTER: Shiratori R

PROVIDER: S-EPMC6904735 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Shiratori Reika R Furuichi Kenta K Yamaguchi Masashi M Miyazaki Natsumi N Aoki Haruna H Chibana Hiroji H Ito Kousei K Aoki Shigeki S

Scientific reports 20191210 1

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, A5 ...[more]

PMID: 31822748

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Project description:Tumor cells are subjected to a broad range of selective pressures. As a result of the imposed stress, subpopulations of surviving cells exhibit individual biochemical phenotypes that reflect metabolic reprograming. The present work aimed at investigating metabolic parameters of cells displaying increasing degrees of metastatic potential. The metabolites present in cell extracts fraction of tongue fibroblasts and of cell lines derived from human tongue squamous cell carcinoma lineages displaying increasing metastatic potential (SCC9 ZsG, LN1 and LN2) were analyzed by 1H NMR (nuclear magnetic resonance) spectroscopy. Living, intact cells were also examined by the non-invasive method of fluorescence lifetime imaging microscopy (FLIM) based on the auto fluorescence of endogenous NADH. The cell lines reproducibly exhibited distinct metabolic profiles confirmed by Partial Least-Square Discriminant Analysis (PLS-DA) of the spectra. Measurement of endogenous free and bound NAD(P)H relative concentrations in the intact cell lines showed that ZsG and LN1 cells displayed high heterogeneity in the energy metabolism, indicating that the cells would oscillate between glycolysis and oxidative metabolism depending on the microenvironment's composition. However, LN2 cells appeared to have more contributions to the oxidative status, displaying a lower NAD(P)H free/bound ratio. Functional experiments of energy metabolism, mitochondrial physiology, and proliferation assays revealed that all lineages exhibited similar energy features, although resorting to different bioenergetics strategies to face metabolic demands. These differentiated functions may also promote metastasis. We propose that lipid metabolism is related to the increased invasiveness as a result of the accumulation of malonate, methyl malonic acid, n-acetyl and unsaturated fatty acids (CH2)n in parallel with the metastatic potential progression, thus suggesting that the NAD(P)H reflected the lipid catabolic/anabolic pathways.

Project description:Human monocyte-derived dendritic cells (moDCs) have been used as an in vitro model for studying tolerance and immunity. However, the underlying metabolic states of tolerogenic (dexamethasone and vitamin D3-treated), immature and immunogenic (mature, LPS-treated) moDCs have not been completely characterized. Through transcriptomic analyses, we determined that tolerogenic moDCs exhibit augmented catabolic pathways with respect to oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and glycolysis. Functionally, tolerogenic moDCs showed the highest mitochondrial membrane potential, production of reactive oxygen species and superoxide, and increased mitochondrial spare respiratory capacity. Tolerogenic and mature moDCs manifested differential FAO gene expression with FAO activity being significantly higher in tolerogenic and immature moDCs than in mature. In addition, tolerogenic and mature moDCs demonstrated similar levels of glycolytic rate, but not glycolytic capacity and reserve, which were more pronounced in tolerogenic and immature moDCs. Finally, tolerogenic and immature moDCs, but not mature moDCs, showed high plasticity to compensate the intracellular ATP content after inhibition of different energetic metabolic pathways. Overall, tolerogenic moDCs exhibit a metabolic signature of increased, stable OXPHOS programing and high plasticity for metabolic adaptation. These findings provide a framework for future research of metabolic properties of human DCs. Total RNA of sixteen samples from four moDC types (tolerogenic, LPS-tolerogenic, immature and mature) were extracted by Trizol (Invitrogen) followed by a clean-up procedure using RNeasy Micro Kit (Qiagen). All RNA samples had an integrity number ≥9.6 assessed by Agilent Bioanalyzer. Total RNA samples were amplified using TargetAmp™ and the biotinilated cRNA was prepared by Nano-g™ Biotin-aRNA Labeling Kit for the Illumina® System (Epicentre). After the hybridization to the Illumina Human HT-12 v4 Beadchips for 17 h at 58°C, the arrays were washed, stained (Illumina Wash Protocol) and then scanned using BeadArray Scanner 500GX. Array data were extracted at the probe level without background correction using Illumina GenomeStudio software. These raw data were quantile normalized and log2 transformed. Technical replicates were obtained from the hybridization in duplicate of three samples. Pearson correlation analysis showed high correlation between the technical replicates (r>0.99). Differentially expressed genes (DEGs) were identified using Limma16 with Benjamini-Hochberg multiple testing correction (p<0.05). DEGs were further clustered into different groups according to the patterns of expression change among the different moDC types using STEM software17. The analysis was performed in R v.2.12.2 (http://www.R-project.org) with Bioconductor 2.12 (http://www.bioconductor.org) and enabled by Pipeline Pilot (www.accelrys.com).

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

Publications

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

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