Mammalian hexokinases and their abnormal expression in cancer

Timothy Andrew Davies Smith

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

The phosphorylation of glucose, a crucial step in cellular metabolism, is catalysed by hexokinases (HK), of which there are four (HKI-IV) in mammalian tissues. The brain HK, (HK1), like HKII and HKIII, has a molecular weight of approximately 100 kDa. HKII is insulin-sensitive and found in adipose and muscle cells. HKIV, also known as glucokinase, has a molecular weight of 50 kDa and is specific to liver and pancreas. Most brain HK is bound to mitochondria via porins, enabling coordination between glucose consumption and oxidation. Tumour cells are known to be highly glycolytic, and correspondingly increased expression of glycolytic enzymes, including HK, have been detected in resected tumours from patients with lung, gastrointestinal and breast cancer. In the latter group, further increases in HK activity were associated with metastatic disease. Some studies have demonstrated increased HK activity in renal tumours, and also have reported changes in the isoenzymic expression of HK. Experimental studies of the initiation and progression of liver tumours have demonstrated a shift in expression from that of HKIV to HKI and HKII, with increased HK binding to mitochondria and a > 100-fold increase in HK activity. However, studies using xenografts derived from gliomas found decreased HK activity corresponding with loss of chromosome 10, the carrier of the HKI gene. Compared with normal tissues, a number of mechanisms are associated with changes in HK activity seen in tumours of the liver and other sites, and these include HK gene dosage, increased transcription, modulation of HK promoter activity by a broader range of effectors, and increased mitochondrial binding of HK. Increased HK activity, together with increased glucose transport by tumour cells, has been exploited in cancer imaging using the positron-labelled glucose analogue (18F)fluoro-2-deoxy-D-glucose (FDG), which is transported into cells and then phosphorylated, but undergoes little further metabolism. Accumulated FDG then can be detected using positron emission tomography (PET).
Original languageEnglish
Pages (from-to)170-178
Number of pages9
JournalBritish Journal of Biomedical Science
Volume58
Publication statusPublished - 1 Jan 2000

Fingerprint

Hexokinase
Neoplasms
Tumors
Liver
Glucose
Mitochondria
Cells
Deoxyglucose
Metabolism
Brain
Genes
Molecular Weight
Molecular weight
Tissue
Glucokinase
Porins
Chromosomes, Human, Pair 10
Phosphorylation
Positron emission tomography
Gastrointestinal Neoplasms

Keywords

  • Glycolysis
  • Hexokinase
  • Neoplasms

Cite this

Mammalian hexokinases and their abnormal expression in cancer. / Smith, Timothy Andrew Davies.

In: British Journal of Biomedical Science, Vol. 58, 01.01.2000, p. 170-178.

Research output: Contribution to journalArticle

Smith, Timothy Andrew Davies. / Mammalian hexokinases and their abnormal expression in cancer. In: British Journal of Biomedical Science. 2000 ; Vol. 58. pp. 170-178.
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