Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose

Johnathan C. Maher, Medhi Wangpaichitr, Niramol Savaraj, Metin Kurtoglu, Theodore Lampidis

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Hypoxic regions within solid tumors harbor cells that are resistant to standard chemotherapy and radiotherapy. Because oxygen is required to produce ATP by oxidative phosphorylation, under hypoxia, cells rely more on glycolysis to generate ATP and are thereby sensitive to 2-deoxy-D-glucose (2-DG), an inhibitor of this pathway. Universally, cells respond to lowered oxygen tension by increasing the amount of glycolytic enzymes and glucose transporters via the well-characterized hypoxia-inducible factor-1 (HIF). To evaluate the effects of HIF on 2-DG sensitivity, the following three models were used: (a) cells treated with oligomycin to block mitochondrial function in the presence (HIF+) or absence (HIF-) of hypoxia,(b) cells treated with small interfering RNA specific for HIF-1α and control cells cultured under hypoxia, and (c) a mutant cell line unable to initiate the HIF response and its parental HIF+ counterpart under hypoxic conditions. In all three models, HIF increased resistance to 2-DG and other glycolytic inhibitors but not to other chemotherapeutic agents. Additionally, HIF reduced the effects of 2-DG on glycolysis (as measured by ATP and lactate assays). Because HIF increases glycolytic enzymes, it follows that greater amounts of 2-DG would be required to inhibit glycolysis, thereby leading to increased resistance to it under hypoxia. Indeed, hexokinase, aldolase, and lactate dehydrogenase were found to be increased as a function of HIF under the hypoxic conditions and cell types we used; however, phosphoglucose isomerase was not. Although both hexokinase and phosphoglucose isomerase are known to interact with 2-DG, our findings of increased levels of hexokinase more likely implicate this enzyme in the mechanism of HIF-mediated resistance to 2-DG. Moreover, because 2-DG is now in phase I clinical trials, our results suggest that glycolytic inhibitors may be more effective clinically when combined with agents that inhibit HIF.

Original languageEnglish
Pages (from-to)732-741
Number of pages10
JournalMolecular Cancer Therapeutics
Volume6
Issue number2
DOIs
StatePublished - Feb 1 2007

Fingerprint

Hypoxia-Inducible Factor 1
Deoxyglucose
Hexokinase
Glycolysis
Glucose-6-Phosphate Isomerase
Cell Hypoxia
Adenosine Triphosphate
Enzymes
Oxygen
Oligomycins
Clinical Trials, Phase I
Fructose-Bisphosphate Aldolase
Facilitative Glucose Transport Proteins
Oxidative Phosphorylation
L-Lactate Dehydrogenase
Small Interfering RNA
Cultured Cells
Lactic Acid

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. / Maher, Johnathan C.; Wangpaichitr, Medhi; Savaraj, Niramol; Kurtoglu, Metin; Lampidis, Theodore.

In: Molecular Cancer Therapeutics, Vol. 6, No. 2, 01.02.2007, p. 732-741.

Research output: Contribution to journalArticle

@article{6ab30180872348279387ba16b7f2f915,
title = "Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose",
abstract = "Hypoxic regions within solid tumors harbor cells that are resistant to standard chemotherapy and radiotherapy. Because oxygen is required to produce ATP by oxidative phosphorylation, under hypoxia, cells rely more on glycolysis to generate ATP and are thereby sensitive to 2-deoxy-D-glucose (2-DG), an inhibitor of this pathway. Universally, cells respond to lowered oxygen tension by increasing the amount of glycolytic enzymes and glucose transporters via the well-characterized hypoxia-inducible factor-1 (HIF). To evaluate the effects of HIF on 2-DG sensitivity, the following three models were used: (a) cells treated with oligomycin to block mitochondrial function in the presence (HIF+) or absence (HIF-) of hypoxia,(b) cells treated with small interfering RNA specific for HIF-1α and control cells cultured under hypoxia, and (c) a mutant cell line unable to initiate the HIF response and its parental HIF+ counterpart under hypoxic conditions. In all three models, HIF increased resistance to 2-DG and other glycolytic inhibitors but not to other chemotherapeutic agents. Additionally, HIF reduced the effects of 2-DG on glycolysis (as measured by ATP and lactate assays). Because HIF increases glycolytic enzymes, it follows that greater amounts of 2-DG would be required to inhibit glycolysis, thereby leading to increased resistance to it under hypoxia. Indeed, hexokinase, aldolase, and lactate dehydrogenase were found to be increased as a function of HIF under the hypoxic conditions and cell types we used; however, phosphoglucose isomerase was not. Although both hexokinase and phosphoglucose isomerase are known to interact with 2-DG, our findings of increased levels of hexokinase more likely implicate this enzyme in the mechanism of HIF-mediated resistance to 2-DG. Moreover, because 2-DG is now in phase I clinical trials, our results suggest that glycolytic inhibitors may be more effective clinically when combined with agents that inhibit HIF.",
author = "Maher, {Johnathan C.} and Medhi Wangpaichitr and Niramol Savaraj and Metin Kurtoglu and Theodore Lampidis",
year = "2007",
month = "2",
day = "1",
doi = "10.1158/1535-7163.MCT-06-0407",
language = "English",
volume = "6",
pages = "732--741",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose

AU - Maher, Johnathan C.

AU - Wangpaichitr, Medhi

AU - Savaraj, Niramol

AU - Kurtoglu, Metin

AU - Lampidis, Theodore

PY - 2007/2/1

Y1 - 2007/2/1

N2 - Hypoxic regions within solid tumors harbor cells that are resistant to standard chemotherapy and radiotherapy. Because oxygen is required to produce ATP by oxidative phosphorylation, under hypoxia, cells rely more on glycolysis to generate ATP and are thereby sensitive to 2-deoxy-D-glucose (2-DG), an inhibitor of this pathway. Universally, cells respond to lowered oxygen tension by increasing the amount of glycolytic enzymes and glucose transporters via the well-characterized hypoxia-inducible factor-1 (HIF). To evaluate the effects of HIF on 2-DG sensitivity, the following three models were used: (a) cells treated with oligomycin to block mitochondrial function in the presence (HIF+) or absence (HIF-) of hypoxia,(b) cells treated with small interfering RNA specific for HIF-1α and control cells cultured under hypoxia, and (c) a mutant cell line unable to initiate the HIF response and its parental HIF+ counterpart under hypoxic conditions. In all three models, HIF increased resistance to 2-DG and other glycolytic inhibitors but not to other chemotherapeutic agents. Additionally, HIF reduced the effects of 2-DG on glycolysis (as measured by ATP and lactate assays). Because HIF increases glycolytic enzymes, it follows that greater amounts of 2-DG would be required to inhibit glycolysis, thereby leading to increased resistance to it under hypoxia. Indeed, hexokinase, aldolase, and lactate dehydrogenase were found to be increased as a function of HIF under the hypoxic conditions and cell types we used; however, phosphoglucose isomerase was not. Although both hexokinase and phosphoglucose isomerase are known to interact with 2-DG, our findings of increased levels of hexokinase more likely implicate this enzyme in the mechanism of HIF-mediated resistance to 2-DG. Moreover, because 2-DG is now in phase I clinical trials, our results suggest that glycolytic inhibitors may be more effective clinically when combined with agents that inhibit HIF.

AB - Hypoxic regions within solid tumors harbor cells that are resistant to standard chemotherapy and radiotherapy. Because oxygen is required to produce ATP by oxidative phosphorylation, under hypoxia, cells rely more on glycolysis to generate ATP and are thereby sensitive to 2-deoxy-D-glucose (2-DG), an inhibitor of this pathway. Universally, cells respond to lowered oxygen tension by increasing the amount of glycolytic enzymes and glucose transporters via the well-characterized hypoxia-inducible factor-1 (HIF). To evaluate the effects of HIF on 2-DG sensitivity, the following three models were used: (a) cells treated with oligomycin to block mitochondrial function in the presence (HIF+) or absence (HIF-) of hypoxia,(b) cells treated with small interfering RNA specific for HIF-1α and control cells cultured under hypoxia, and (c) a mutant cell line unable to initiate the HIF response and its parental HIF+ counterpart under hypoxic conditions. In all three models, HIF increased resistance to 2-DG and other glycolytic inhibitors but not to other chemotherapeutic agents. Additionally, HIF reduced the effects of 2-DG on glycolysis (as measured by ATP and lactate assays). Because HIF increases glycolytic enzymes, it follows that greater amounts of 2-DG would be required to inhibit glycolysis, thereby leading to increased resistance to it under hypoxia. Indeed, hexokinase, aldolase, and lactate dehydrogenase were found to be increased as a function of HIF under the hypoxic conditions and cell types we used; however, phosphoglucose isomerase was not. Although both hexokinase and phosphoglucose isomerase are known to interact with 2-DG, our findings of increased levels of hexokinase more likely implicate this enzyme in the mechanism of HIF-mediated resistance to 2-DG. Moreover, because 2-DG is now in phase I clinical trials, our results suggest that glycolytic inhibitors may be more effective clinically when combined with agents that inhibit HIF.

UR - http://www.scopus.com/inward/record.url?scp=33847353815&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847353815&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-06-0407

DO - 10.1158/1535-7163.MCT-06-0407

M3 - Article

C2 - 17308069

AN - SCOPUS:33847353815

VL - 6

SP - 732

EP - 741

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 2

ER -