Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells

Sánchez‐Sánchez, Ana M.; Antolı́n, Isaac; Puente‐Moncada, Noelia; Suárez, S.; Gomez-Lobo, Marina; Rodríguez, Carmen; Martı́n, Vanesa

doi:10.1371/journal.pone.0135420

Cited by 64 publications

(48 citation statements)

References 38 publications

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“…The over-production of lactate is due to activity of lactate dehydrogenase enzyme, which has five isoforms (LDH-1 to LDH-5) differentially expressed in normal tissues and up-regulated during carcinogenesis [120]. For example, increased glucose uptake, induction of glycolysis-related genes, excessive lactate production, and HIF-1α activation associated with aggressive phenotype and poor prognosis have been observed in patients with HCC and in Ewing sarcoma cells [121,122]. These observations have led to the conclusion that forcing cancer cells into mitochondrial oxidative metabolism can efficiently suppress tumor progression, whereas targeting glycolytic enzymes can be effective strategy to combat cancer growth.…”

Section: Cancer Acidification and Its Role In Reverse To Oxphosmentioning

confidence: 99%

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Moldogazieva

Mokhosoev

Terentiev

2020

Cancers

117

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It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

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Section: Cancer Acidification and Its Role In Reverse To Oxphosmentioning

confidence: 99%

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Moldogazieva

Mokhosoev

Terentiev

2020

Cancers

117

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“…In addition, several groups have shown that 2-NBDG is useful for monitoring aberrant cellular uptake of d-glucose in tumors in vitro and in vivo [137][138][139][140][141][142][143][144][145]. 2-NBDG has been effectively applied to clinical specimens as well such as biopsy tissues obtained from patients with oral cancer [146,147], esophagus cancer [148], head and neck cancer [149], breast cancer [150], colorectal cancer [151], and for metabolic phenotyping or screening of cancerous cells in pleural effusion or peripheral blood obtained from lung cancer patients [152,153].…”

Section: Uptake Of 2-nbdg Into Mammalian Cells Through Gluts and Its mentioning

confidence: 99%

L-Glucose: Another Path to Cancer Cells

Ono

Takigawa

Yamada

2020

Cancers

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Cancerous tumors comprise cells showing metabolic heterogeneity. Among numerous efforts to understand this property, little attention has been paid to the possibility that cancer cells take up and utilize otherwise unusable substrates as fuel. Here we discuss this issue by focusing on l-glucose, the mirror image isomer of naturally occurring d-glucose; l-glucose is an unmetabolizable sugar except in some bacteria. By combining relatively small fluorophores with l-glucose, we generated fluorescence-emitting l-glucose tracers (fLGs). To our surprise, 2-NBDLG, one of these fLGs, which we thought to be merely a control substrate for the fluorescent d-glucose tracer 2-NBDG, was specifically taken up into tumor cell aggregates (spheroids) that exhibited nuclear heterogeneity, a major cytological feature of malignancy in cancer diagnosis. Changes in mitochondrial activity were also associated with the spheroids taking up fLG. To better understand these phenomena, we review here the Warburg effect as well as key studies regarding glucose uptake. We also discuss tumor heterogeneity involving aberrant uptake of glucose and mitochondrial changes based on the data obtained by fLG. We then consider the use of fLGs as novel markers for visualization and characterization of malignant tumor cells.

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“…18 It was recently shown that the cytotoxicity of melatonin in tumor cells is associated with its suppression of aerobic glycolysis. 19 However, the effect of AgNPs on tumor cell metabolism has not yet been completely determined.…”

mentioning

confidence: 99%

Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species

Lee

Lee²,

Yun³

et al. 2015

IJN

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The silver nanoparticle (AgNP) is a candidate for anticancer therapy because of its effects on cell survival and signaling. Although numerous reports are available regarding their effect on cell death, the effect of AgNPs on metabolism is not well understood. In this study, we investigated the effect of AgNPs on glucose metabolism in hepatoma cell lines. Lactate release from both HepG2 and Huh7 cells was reduced with 5 nm AgNPs as early as 1 hour after treatment, when cell death did not occur. Treatment with 5 nm AgNPs decreased glucose consumption in HepG2 cells but not in Huh7 cells. Treatment with 5 nm AgNPs reduced nuclear factor erythroid 2-like 2 expression in both cell types without affecting its activation at the early time points after AgNPs’ treatment. Increased reactive oxygen species (ROS) production was detected 1 hour after 5 nm AgNPs’ treatment, and lactate release was restored in the presence of an ROS scavenger. Our results suggest that 5 nm AgNPs affect glucose metabolism by producing ROS.

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Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells

Cited by 64 publications

References 38 publications

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

L-Glucose: Another Path to Cancer Cells

Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species

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