2-Deoxy-D-Glucose inhibits aggressive triple-negative breast cancer cells by targeting glycolysis and the cancer stem cell phenotype

O’Neill, Sadhbh; Porter, Richard K.; McNamee, Niamh; Martínez, Vanesa G.; O’Driscoll, Lorraine

doi:10.1038/s41598-019-39789-9

Cited by 77 publications

(51 citation statements)

References 31 publications

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“…There is conflicting evidence regarding the dependence of the CSCs of breast (and other tumor types) on glycolysis vs. oxidative phosphorylation. Reports have demonstrated that chemically inhibiting glycolysis reduces populations of breast cancer cells with CSC characteristics (35,36). Furthermore, during epithelial-mesenchymal transition (EMT), breast cancer cells undergo glycolytic metabolic reprogramming where they acquire CSC-like characteristics and exhibit increased tumorigenicity (37).…”

Section: Breast Cancer Stem Cells: Inherent Metabolic Plasticitymentioning

confidence: 99%

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

et al. 2019

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Within heterogeneous tumors, cancer stem cell (CSC) populations exhibit the greatest tumor initiation potential, promote metastasis, and contribute to therapy resistance. For breast cancer specifically, CSCs are identified by CD44 high CD24 low cell surface marker expression and increased aldehyde dehydrogenase activity. In general, bulk breast tumor cells possess altered energetics characterized by aerobic glycolysis. In contrast, breast CSCs appear to have adaptive metabolic plasticity that allows these tumor-initiating cells to switch between glycolysis and oxidative phosphorylation, depending on factors present in the tumor microenvironment (e.g., hypoxia, reactive oxygen species, availability of glucose). In this article, we review the regulatory molecules that may facilitate the metabolic plasticity of breast CSCs. These regulatory factors include epigenetic chromatin modifiers, non-coding RNAs, transcriptional repressors, transcription factors, energy and stress sensors, and metabolic enzymes. Furthermore, breast cancer cells acquire CSC-like characteristics and altered energetics by undergoing epithelial-mesenchymal transition (EMT). This energy costly process is paired with reprogrammed glucose metabolism by epigenetic modifiers that regulate expression of both EMT and other metabolism-regulating genes. The survival advantage imparted to breast CSCs by metabolic plasticity suggests that targeting the factors that mediate the energetic switch should hinder tumorigenesis and lead to improved patient outcomes.

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Section: Breast Cancer Stem Cells: Inherent Metabolic Plasticitymentioning

confidence: 99%

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

et al. 2019

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“…Thus, combination of lower dose of 2-DG with other anticancer drugs, or with radiotherapy, is promising for clinical use (19). A recent report showed that 2-DG is also effective in inhibiting migration and invasion ability of an invasive subclone of the TNBC cell line, Hs578T (20). Due to limited therapeutic options for targeting metastasis, use of 2-DG for blocking cancer invasiveness is attractive, however, the study only showed the result of one BC cell line, Hs578T, and thus, further studies are required to clarify the role of glycolysis on BC invasion.…”

Section: Introductionmentioning

confidence: 99%

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: Impact of non-cytotoxic doses of 2-DG on diminishing invasiveness

Fujita

Imadome

Somasundaram

et al. 2020

Preprint

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Abstract BackgroundMetabolic reprogramming is being recognized as a fundamental hallmark of cancer, and efforts to identify drugs that can target cancer metabolism are underway. In this study, we used human breast cancer (BC) cell lines and established their invading phenotype (INV) collected from transwell inserts to compare metabolome differences and evaluate prognostic significance of the metabolome in aggressive BC invasiveness.MethodsThe invasiveness of seven human BC cell lines were compared using the transwell invasion assay. Among these, INV was collected from SUM149, which exhibited the highest invasiveness. Levels of metabolites in INV were compared with those of whole cultured SUM149 cells (WCC) using CE-TOFMS. The impact of glycolysis in INV was determined by glucose uptake assay using fluorescent derivative of glucose (2-NBDG), and significance of glycolysis, or tricarboxylic acid (TCA) and electron transport chain (ETC) in the invasive process were further determined in aggressive BC cell lines, SUM149, MDA-MB-231, HCC1937, using invasion assays in the presence or absence of inhibitors of glycolysis, TCA cycle or ETC.ResultsSUM149 INV sub-population exhibited a persistent hyperinvasive phenotype. INV were hyper-glycolytic with increased glucose (2-NBDG) uptake; diminished glucose-6-phosphate (G6P) levels but elevated pyruvate and lactate, along with higher expression of phosphorylated-pyruvate dehydrogenase (pPDH) compared to WCC. Notably, inhibiting of glycolysis with lower doses of 2-DG (1 mM), non-cytotoxic to MDA-MB-231 and HCC1937, was effective in diminishing invasiveness of aggressive BC cell lines. In contrast, 3-Nitropropionic acid (3-NA), an inhibitor of succinate dehydrogenase, the enzyme that oxidizes succinate to fumarate in TCA cycle, and functions as complex II of ETC, had no significant effect on their invasiveness, although levels of TCA metabolites or detection of mitochondrial membrane potential with JC-1 staining, indicated that INV cells originally had functional TCA cycles and membrane potential.ConclusionsHyper-glycolytic phenotype of invading cells caters to rapid energy production required for invasion while TCA cycle/ETC cater to cellular energy needs for sustenance in aggressive BC. Lower, non-cytotoxic doses of 2-DG can hamper invasion and can potentially be used as an adjuvant with other anti-cancer therapies without the usual side-effects associated with cytotoxic doses.

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“…In accordance, we observed that 1 mM of 2-DG did not reduce cell survival of MDA-MB-231 and HCC1937 cell lines, but of note, it was signi cantly effective in blocking their invasion. Sadhbh O'Neill et al have reported that 2-DG is effective to inhibit migration and invasion ability of invasive BC subclone, Hs578T, but they used much higher concentration of 2-DG i.e., 15 mM (15 times the dose used in the current study), and have not focused on the effect of 2-DG with lower dose (20). The associated side effects of such a high dose of 2-DG would impede its use in clinical trials.…”

Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: Impact of non-cytotoxic doses of 2-DG on diminishing invasiveness

Fujita

Imadome

Somasundaram

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Metabolic reprogramming is being recognized as a fundamental hallmark of cancer, and efforts to identify drugs that can target cancer metabolism are underway. In this study, we used human breast cancer (BC) cell lines and established their invading phenotype (INV) collected from transwell inserts to compare metabolome differences and evaluate prognostic significance of the metabolome in aggressive BC invasiveness. Methods The invasiveness of seven human BC cell lines were compared using the transwell invasion assay. Among these, INV was collected from SUM149, which exhibited the highest invasiveness. Levels of metabolites in INV were compared with those of whole cultured SUM149 cells (WCC) using CE-TOFMS. The impact of glycolysis in INV was determined by glucose uptake assay using fluorescent derivative of glucose (2-NBDG), and significance of glycolysis, or tricarboxylic acid (TCA) and electron transport chain (ETC) in the invasive process were further determined in aggressive BC cell lines, SUM149, MDA-MB-231, HCC1937, using invasion assays in the presence or absence of inhibitors of glycolysis, TCA cycle or ETC. Results SUM149 INV sub-population exhibited a persistent hyperinvasive phenotype. INV were hyper-glycolytic with increased glucose (2-NBDG) uptake; diminished glucose-6-phosphate (G6P) levels but elevated pyruvate and lactate, along with higher expression of phosphorylated-pyruvate dehydrogenase (pPDH) compared to WCC. Notably, inhibiting of glycolysis with lower doses of 2-DG (1 mM), non-cytotoxic to MDA-MB-231 and HCC1937, was effective in diminishing invasiveness of aggressive BC cell lines. In contrast, 3-Nitropropionic acid (3-NA), an inhibitor of succinate dehydrogenase, the enzyme that oxidizes succinate to fumarate in TCA cycle, and functions as complex II of ETC, had no significant effect on their invasiveness, although levels of TCA metabolites or detection of mitochondrial membrane potential with JC-1 staining, indicated that INV cells originally had functional TCA cycles and membrane potential. Conclusions Hyper-glycolytic phenotype of invading cells caters to rapid energy production required for invasion while TCAcycle/ETC cater to cellular energy needs for sustenance in aggressive BC. Lower, non-cytotoxic doses of 2-DG can hamper invasion and can potentially be used as an adjuvant with other anti-cancer therapies without the usual side-effects associated with cytotoxic doses.

show abstract

2-Deoxy-D-Glucose inhibits aggressive triple-negative breast cancer cells by targeting glycolysis and the cancer stem cell phenotype

Cited by 77 publications

References 31 publications

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

The Flick of a Switch: Conferring Survival Advantage to Breast Cancer Stem Cells Through Metabolic Plasticity

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: Impact of non-cytotoxic doses of 2-DG on diminishing invasiveness

Metabolic characterization of aggressive breast cancer cells exhibiting invasive phenotype: Impact of non-cytotoxic doses of 2-DG on diminishing invasiveness

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