The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

Yu, Li; Chen, Xun; Wang, Liantang; Chen, Shangwu

doi:10.18632/oncotarget.7676

Cited by 100 publications

(106 citation statements)

References 185 publications

(202 reference statements)

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“…Also, lactate production remained low when cells were exposed to 0.1 μmol/L IM for 4 weeks (Figure B). Furthermore, we observed reduced expression of HIF‐1α protein, which contributes to increased glycolysis and proliferation of cancer cells, and reduced expression of mRNA encoding glycolytic enzymes hexokinase 2 and lactate dehydrogenase A in K562‐IM3w cells (Figure C,D). Inhibiting glycolysis using 2‐deoxy‐ d ‐glucose increases the efficacy of several anti‐cancer agents; however, inhibiting glycolysis in K562 cells using 2‐deoxy‐ d ‐glucose did not increase their sensitivity to IM (Figure E), despite marked inhibition of glycolysis (Figure ).…”

Section: Resultsmentioning

confidence: 97%

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

et al. 2017

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Tyrosine kinase inhibitors (TKI), including imatinib (IM), improve the outcome of CML therapy. However, TKI treatment is long‐term and can induce resistance to TKI, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome‐positive CML cell line, and its subsequent sensitivity to anti‐cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKI. Cancer energy metabolism, characterized by abnormal glycolysis, is linked to cancer cell survival. Interestingly, glycolytic activity was suppressed by continuous exposure to IM, and autophagy increased to maintain cell viability by compensating for glycolytic suppression. Notably, increased sensitivity to TKI was not caused by glycolytic inhibition but by altered intracellular signaling, causing glycolytic suppression and increased autophagy, as evidenced by suppression of p70 S6 kinase 1 (S6K1) and activation of AMP‐activated protein kinase (AMPK). Using another human CML cell line (KCL22 cells) and BCR/ABL+ Ba/F3 cells (mimicking Philadelphia chromosome‐positive CML cells) confirmed that suppressing S6K1 and activating AMPK increased sensitivity to TKI. Furthermore, suppressing S6K1 and activating AMPK had a synergistic anti‐cancer effect by inhibiting autophagy in the presence of TKI. The present study provides new insight into the importance of signaling pathways that affect cellular energy metabolism, and suggests that co‐treatment with agents that disrupt energy metabolic signaling (using S6K1 suppressors and AMPK activators) plus blockade of autophagy may be strategies for TKI‐based CML therapy.

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Section: Resultsmentioning

confidence: 97%

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

et al. 2017

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“…Glycolysis is a low energy yield process but is more simple and fast. Therefore, glycolysis is exacerbated in tumor tissue and increases with tumor progression [32]. …”

Section: Hypoxia Reprogramming Carbohydrate Metabolismmentioning

confidence: 99%

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

Silva-filho¹,

Sena²,

Lima

et al. 2017

Cell Physiol Biochem

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Post-translational and co-translational enzymatic addition of glycans (glycosylation) to proteins, lipids, and other carbohydrates, is a powerful regulator of the molecular machinery involved in cell cycle, adhesion, invasion, and signal transduction, and is usually seen in both in vivo and in vitro cancer models. Glycosyltransferases can alter the glycosylation pattern of normal cells, subsequently leading to the establishment and progression of several diseases, including cancer. Furthermore, a growing amount of research has shown that different oxygen tensions, mainly hypoxia, leads to a markedly altered glycosylation, resulting in altered glycan-receptor interactions. Alteration of intracellular glucose metabolism, from aerobic cellular respiration to anaerobic glycolysis, inhibition of integrin 3α1β translocation to the plasma membrane, decreased 1,2-fucosylation of cell-surface glycans, and galectin overexpression are some consequences of the hypoxic tumor microenvironment. Additionally, increased expression of gangliosides carrying N-glycolyl sialic acid can also be significantly affected by hypoxia. For all these reasons, it is possible to realize that hypoxia strongly alters glycobiologic events within tumors, leading to changes in their behavior. This review aims to analyze the complexity and importance of glycoconjugates and their molecular interaction network in the hypoxic context of many solid tumors.

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“…There are many proteins participating in regulating aerobic glycolysis including glucose transporters 1 (GLUT1), lactate dehydrogenase A (LDHA), and PDH kinase (PDK) . GLUT1 facilitates the transport of glucose into cancer cells . LDHA is responsible for catalyzing the final glycolytic step that converts pyruvate into lactate .…”

Section: Introductionmentioning

confidence: 99%

p,p′‐Dichlorodiphenyltrichloroethane promotes aerobic glycolysis via reactive oxygen species–mediated extracellular signal‐regulated kinase/M2 isoform of pyruvate kinase (PKM2) signaling in colorectal cancer cells

Song

Dong

2019

Environmental Toxicology

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Aerobic glycolysis is crucial to tumor cells to acquire energy for proliferation and metastasis. Dichlorodiphenyltrichloroethane (DDT), which is a persistent organic pollutant, has been associated with colorectal cancer (CRC) progressions, but the influence of p,p 0 -DDT on CRC cell metabolism remains unclear. This study showed that exposure to low concentrations of p,p 0 -DDT from 10 −11 to 10 −7 M for 48 hours significantly increased glucose uptake and lactate production in colorectal adenocarcinoma cells, which were accompanied by the upregulation of proteins associated with aerobic glycolysis including glucose transporter1, lactate dehydrogenase A, and PDH kinase. We found p,p 0 -DDT elevated the expression and nucleus translocation of M2 isoform of pyruvate kinase (PKM2), which was responsible for p,p 0 -DDT-induced enhancement of aerobic glycolysis. Moreover, extracellular signal-regulated kinase (ERK1/2) activation by p,p 0 -DDT modulated the impacts of p,p 0 -DDT on PKM2 and aerobic glycolysis. Treatment of p,p 0 -DDT increased intracellular reactive oxygen species (ROS). N-acetyl-L-cysteine, an ROS inhibitor, prevented p,p 0 -DDT-induced promotion of aerobic glycolysis, ERK1/2 activation, upregulation, and nucleus translocation of PKM2. Taken together, these results demonstrated that p,p 0 -DDT promotes aerobic glycolysis via ROS-mediated ERK/PKM2 signaling. K E Y W O R D Saerobic glycolysis, colorectal cancer, PKM2, p,p 0 -dichlorodiphenyltrichloroethane, reactive oxygen species

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The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

Cited by 100 publications

References 185 publications

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

p,p′‐Dichlorodiphenyltrichloroethane promotes aerobic glycolysis via reactive oxygen species–mediated extracellular signal‐regulated kinase/M2 isoform of pyruvate kinase (PKM2) signaling in colorectal cancer cells

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