The Warburg effect and its cancer therapeutic implications

Zhao, Chen; Lu, Weiqin; Garcı́a-Prieto, Celia; Huang, Peng

doi:10.1007/s10863-007-9086-x

Cited by 283 publications

(219 citation statements)

References 61 publications

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“…3-BrOP is known to preferentially kill cancer cells with elevated glycolytic activity (Chen et al, 2007). These data suggested that miR-210 can trigger the metabolic switch from aerobic respiration to glycolysis.…”

Section: Hypoxia and Chemical Mimetic Regulate Mir-210mentioning

confidence: 95%

Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression

et al. 2010

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The mechanisms of compromised mitochondrial function under various pathological conditions, including hypoxia, remain largely unknown. Recent studies have shown that microRNA-210 (miR-210) is induced by hypoxia under the regulation of hypoxia-inducible factor-1a and has an important role in cell survival under hypoxic microenvironment. Hence, we hypothesized that miR-210 has a role in regulating mitochondrial metabolism and investigated miR-210 effects on mitochondrial function in cancer cell lines under normal and hypoxic conditions. Our results demonstrate that miR-210 decreases mitochondrial function and upregulates the glycolysis, thus make cancer cells more sensitive to glycolysis inhibitor. miR-210 can also activate the generation of reactive oxygen species (ROS). ISCU (iron-sulfur cluster scaffold homolog) and COX10 (cytochrome c oxidase assembly protein), two important factors of the mitochondria electron transport chain and the tricarboxylic acid cycle have been identified as potential targets of miR-210. The unique means by which miR-210 regulates mitochondrial function reveals an miRNAmediated link between microenvironmental stress, oxidative phosphorylation, ROS and iron homeostasis.

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Section: Hypoxia and Chemical Mimetic Regulate Mir-210mentioning

confidence: 95%

Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression

et al. 2010

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“…In contrast, cancer cells depend mostly on glycolysis, the aerobic breakdown of glucose into the energy-storing molecule adenosine triphosphate (ATP). This altered energy dependency is known as the 'Warburg effect' and is a hallmark of cancer cells (Warburg, 1956;Kim and Dang, 2006;Chen et al, 2007;Gatenby and Gillies, 2007;DeBerardinis et al, 2008;Gillies et al, 2008;Hsu and Sabatini, 2008;Kroemer and Pouyssegur, 2008).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

et al. 2009

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ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

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“…This phenomenon is characterized by increased glucose uptake and reliance on glycolysis for ATP production despite an available oxygen source (5). Aerobic glycolysis is believed to be a result of mitochondrial dysfunction which confers apoptotic resistance in cancer cells (6).…”

Section: Introductionmentioning

confidence: 99%

Dichloroacetate induces apoptosis in endometrial cancer cells

Wong

Huggins

Debidda

et al. 2008

Gynecologic Oncology

189

170

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Purpose-A recent landmark study demonstrated that Dichloroacetate (DCA) treatment promoted apoptosis in lung, breast, and glioblastoma cancer cell lines by shifting metabolism from aerobic glycolysis to glucose oxidation coupled with NFAT-Kv1.5 axis remodeling. The objective of this study was to determine whether DCA induces apoptosis in endometrial cancer cells and to assess apoptotic mechanism.Methods-A panel of endometrial cancer cell lines with varying degrees of differentiation was treated with DCA and analyzed for apoptosis via flow cytometry. Biological correlates such as gene expression, intracellular Ca 2+ , and mitochondrial membrane potential were examined to assess apoptotic mechanism.Results-Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on noncancerous 293T cells. Two highly invasive endometrial adenocarcinoma cell lines, HEC1A and HEC1B, were found to be resistant to DCA induced apoptosis. Apoptotic responding cell lines had a significant increase in early and late apoptotis, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism. DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway. DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of Interest Statement:The authors declare there are no conflicts of interest. NIH Public Access

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The Warburg effect and its cancer therapeutic implications

Cited by 283 publications

References 61 publications

Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression

Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

Dichloroacetate induces apoptosis in endometrial cancer cells

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