Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

Kang, Hyunkoo; Kim, Hyun Woo; Lee, Sung-Min; Youn, HyeSook; Youn, BuHyun

doi:10.3390/ijms20082042

Cited by 122 publications

(114 citation statements)

References 166 publications

(174 reference statements)

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“…Epithelial‐mesenchymal transition‐dependent tumor invasion and metastasis is accompanied by increased cancer cell stemness and drug resistance . Furthermore, more recent studies report that the EMT is associated with altered metabolism in cancer cells and that EMT‐induced metabolic reprogramming in favor of glycolytic phenotypes promotes tumor aggressiveness . We previously showed that hypoxia and undernutrition increase ANGPTL2 expression in tumor cells and thereby enhance tumor cell metastatic capacity .…”

Section: Discussionsupporting

confidence: 66%

Tumor cell‐derived angiopoietin‐like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells

et al. 2020

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We previously revealed that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) accelerates the metastatic capacity of tumors in an autocrine/paracrine manner by activating tumor cell motility and invasiveness and the epithelial-mesenchymal transition. However, the effects of ANGPTL2 on cancer cell glycolytic metabolism, which is a hallmark of tumor cells, are unknown. Here we report evidence supporting a role for tumor cell-derived ANGPTL2 in establishing a preference for glycolytic metabolism. We report that a highly metastatic lung cancer cell subline expressing abundant ANGPTL2 showed upregulated expression of the glucose transporter GLUT3 as well as enhanced glycolytic metabolism relative to a less metastatic parental line. Most notably, ANGPTL2 overexpression in the less metastatic line activated glycolytic metabolism by increasing GLUT3 expression. Moreover, ANGPTL2 signaling through integrin α5β1 increased GLUT3 expression by increasing transforming growth factor-β (TGF-β) signaling and expression of the downstream transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Conversely, ANGPTL2 knockdown in the highly metastatic subline decreased TGF-β1, ZEB1, and GLUT3 expression and antagonized glycolytic metabolism. In primary tumor cells from patients with lung cancer, ANGPTL2 expression levels correlated with GLUT3 expression. Overall, this work suggests that tumor cell-derived ANGPTL2 accelerates activities associated with glycolytic metabolism in lung cancer cells by activating TGF-β-ZEB1-GLUT3 signaling. K E Y W O R D SANGPTL2, cancer metabolism, GLUT3, lung cancer, ZEB1

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Section: Discussionsupporting

confidence: 66%

Tumor cell‐derived angiopoietin‐like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells

et al. 2020

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“…Epithelial mesenchymal transition (EMT) confers metastatic properties to cancer cells by increasing mobility, invasion, and metastasis (54)(55). Interestingly, SNAI1, the transcription factor that represses Ecadherin expression (the marker of EMT induction), also enhances gene expression patterns that promote glucose uptake and glycolysis (56).…”

Section: Discussionmentioning

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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“…The plasticity of glucose metabolism is important in EMT (34). The genes and biochemical mechanisms impact glucose metabolism during EMT of cancer cells.…”

Section: Glucose Metabolism and Emtmentioning

confidence: 99%

“…HIF1α, Myc and FOXM1 regulate both metabolism and EMT (37). LKB1 / AMPK (Liver kinase B1/AMP-activated protein kinase) downregulates SNAIL and ZEB1and inhibits the invasion and migration of tumor cells, by regulating FOXO3, TGFβ, NF-κB, AKT, and mTOR signaling pathways (34).…”

Section: Glucose Metabolism and Emtmentioning

confidence: 99%

“…Glucose transporters, especially GLUT-1 and GLUT-3, promote tumor progression by increasing glucose influx and activating downstream molecular pathways (38). GLUT-1 increases matrix metalloproteinase 2 (MMP-2) in vitro and in vivo, which contributes to EMT and cellular invasiveness (34,39). GLUT-3 gene could be activated by ZEB1, which is an EMT marker (34).…”

Section: Glucose Metabolism and Emtmentioning

confidence: 99%

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Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

et al. 2020

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Malignant cells support tumor proliferation and progression by adopting to metabolic changes. Tumor cells altered metabolism by increasing glucose uptake and fermentation of glucose to lactate, even in the aerobic state and the presence of functioning mitochondria. Glucose metabolism in tumor plasticity has attracted great interests by clinicians and scientists in the past decades. This review discusses the previous and emerging researches on the tumor plasticity altered by changing glucose metabolism in different cancer cells, including cancer stem cells (CSCs). In addition, we summarize the rising applications of glucose metabolism in tumor diagnosis and treatment. Our objective is to direct future investigation on this altered metabolic phenotype and its application in patient care.

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Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

Cited by 122 publications

References 166 publications

Tumor cell‐derived angiopoietin‐like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells

Tumor cell‐derived angiopoietin‐like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells

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

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

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