Hexokinase II

Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

S. P. Mathupala, Y. H. Ko, Peter L Pedersen

Research output: Contribution to journalArticle

Abstract

A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.

Original languageEnglish (US)
Pages (from-to)4777-4786
Number of pages10
JournalOncogene
Volume25
Issue number34
DOIs
StatePublished - Aug 7 2006

Fingerprint

Hexokinase
Mitochondria
Neoplasms
Adenosine Triphosphate
Phenotype
Glucose
Positron-Emission Tomography
Chemical Warfare
Voltage-Dependent Anion Channels
Neoplasm Metastasis
Porins
Glucose-6-Phosphate
Facilitative Glucose Transport Proteins
Adenine Nucleotides
Mitochondrial Membranes
Hepatocellular Carcinoma
Lactic Acid
Catalytic Domain
Proteins
Cell Death

Keywords

  • Cell death: 3-bromopyruvate
  • Glycolysis
  • Hexokinase II
  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Hexokinase II : Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. / Mathupala, S. P.; Ko, Y. H.; Pedersen, Peter L.

In: Oncogene, Vol. 25, No. 34, 07.08.2006, p. 4777-4786.

Research output: Contribution to journalArticle

Mathupala, S. P. ; Ko, Y. H. ; Pedersen, Peter L. / Hexokinase II : Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. In: Oncogene. 2006 ; Vol. 25, No. 34. pp. 4777-4786.
@article{2189e47a0a804a38b6477beeb73f672f,
title = "Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria",
abstract = "A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.",
keywords = "Cell death: 3-bromopyruvate, Glycolysis, Hexokinase II, Mitochondria",
author = "Mathupala, {S. P.} and Ko, {Y. H.} and Pedersen, {Peter L}",
year = "2006",
month = "8",
day = "7",
doi = "10.1038/sj.onc.1209603",
language = "English (US)",
volume = "25",
pages = "4777--4786",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "34",

}

TY - JOUR

T1 - Hexokinase II

T2 - Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria

AU - Mathupala, S. P.

AU - Ko, Y. H.

AU - Pedersen, Peter L

PY - 2006/8/7

Y1 - 2006/8/7

N2 - A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.

AB - A key hallmark of many cancers, particularly the most aggressive, is the capacity to metabolize glucose at an elevated rate, a phenotype detected clinically using positron emission tomography (PET). This phenotype provides cancer cells, including those that participate in metastasis, a distinct competitive edge over normal cells. Specifically, after rapid entry of glucose into cancer cells on the glucose transporter, the highly glycolytic phenotype is supported by hexokinase (primarily HK II) that is overexpressed and bound to the outer mitochondrial membrane via the porin-like protein voltage-dependent anion channel (VDAC). This protein and the adenine nucleotide transporter move ATP, newly synthesized by the inner membrane located ATP synthase, to active sites on HK II. The abundant amounts of HK II bind both the ATP and the incoming glucose producing the product glucose-6-phosphate, also at an elevated rate. This critical metabolite then serves both as a biosynthetic precursor to support cell proliferation and as a precursor for lactic acid, the latter exiting cancer cells causing an unfavorable environment for normal cells. Although helping facilitate this chemical warfare, HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host. For these reasons, targeting this key enzyme is currently being investigated in several laboratories in a strategy to develop novel therapies that may turn the tide on the continuing struggle to find effective cures for cancer. One such candidate is 3-bromopyruvate that has been shown recently to eradicate advanced stage, PET positive hepatocellular carcinomas in an animal model without apparent harm to the animals.

KW - Cell death: 3-bromopyruvate

KW - Glycolysis

KW - Hexokinase II

KW - Mitochondria

UR - http://www.scopus.com/inward/record.url?scp=33746924468&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746924468&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1209603

DO - 10.1038/sj.onc.1209603

M3 - Article

VL - 25

SP - 4777

EP - 4786

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 34

ER -