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

Oncogene volume 25, pages 4777–4786 (2006)Cite this article

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.

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Acknowledgements

SPM is supported by Grant IRG-85-003-14 from the American Cancer Society and a grant from the LEARN Foundation, Michigan, YHK by Grant BCTR0402523 from the Susan Komen Breast Cancer Foundation, and PLP by NIH Grants R01CA08018 and R01CA010951.

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  1. Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    S P Mathupala

  2. Department of Biological Chemistry, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    Y H Ko & P L Pedersen

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Correspondence to P L Pedersen.

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Mathupala, S., Ko, Y. & Pedersen, P. Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25, 4777–4786 (2006). https://doi.org/10.1038/sj.onc.1209603

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