Mathupala SP, Ko YH, Pedersen PL.. Hexokinase-2 bound to mitochondria: cancer's stygian link to the ‘Warburg Effect’ and a pivotal target for effective therapy. Semin Cancer Biol 19: 17-24

Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205-2185, United States
Seminars in Cancer Biology (Impact Factor: 9.33). 02/2009; 19(1):17-24. DOI: 10.1016/j.semcancer.2008.11.006


The most common metabolic hallmark of malignant tumors, i.e., the “Warburg effect” is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen. The pivotal player in this frequent cancer phenotype is mitochondrial-bound hexokinase [Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci USA 1977;74(9):3735–9; Bustamante E, Morris HP, Pedersen PL. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 1981;256(16):8699–704]. Now, in clinics worldwide this prominent phenotype forms the basis of one of the most common detection systems for cancer, i.e., positron emission tomography (PET). Significantly, HK-2 is the major bound hexokinase isoform expressed in cancers that exhibit a “Warburg effect”. This includes most cancers that metastasize and kill their human host. By stationing itself on the outer mitochondrial membrane, HK-2 also helps immortalize cancer cells, escapes product inhibition and gains preferential access to newly synthesized ATP for phosphorylating glucose. The latter event traps this essential nutrient inside the tumor cells as glucose-6-P, some of which is funneled off to serve as carbon precursors to help promote the production of new cancer cells while much is converted to lactic acid that exits the cells. The resultant acidity likely wards off an immune response while preparing surrounding tissues for invasion. With the re-emergence and acceptance of both the “Warburg effect” as a prominent phenotype of most clinical cancers, and “metabolic targeting” as a rational therapeutic strategy, a number of laboratories are focusing on metabolite entry or exit steps. One remarkable success story [Ko YH, Smith BL, Wang Y, Pomper MG, Rini DA, Torbenson MS, et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 2004;324(1):269–75] is the use of the small molecule 3-bromopyruvate (3-BP) that selectively enters and destroys the cells of large tumors in animals by targeting both HK-2 and the mitochondrial ATP synthasome. This leads to very rapid ATP depletion and tumor destruction without harm to the animals. This review focuses on the multiple roles played by HK-2 in cancer and its potential as a metabolic target for complete cancer destruction.

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Available from: Saroj Mathupala, May 27, 2014
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    • "The ATP synthasome has been postulated to exert greater flux control of respiration in human breast cancer tissues than in normal oxidative tissues (Kaambre et al., 2012). The proposed ATP synthasome was partially isolated and characterized from inner membrane vesicles of rat liver mitochondria (a non-cancer tissue) (Ko et al., 2003; Chen et al., 2004; Mathupala et al., 2009). However, the complete isolation, immuno-electron microscopic characterization or mild detergent solubilization of mitochondria and Blue Native PolyAcrylamide Gel Electrophoresis (BN-PAGE) to separate mitochondrial super-complexes and to verify the existence of ATP synthasomes from the mitochondrial membranes of tumor cells are still lacking. "
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    ABSTRACT: Enhanced glycolysis, the classic bioenergetic phenotype of cancer cells was described by Otto Warburg approximately 90 years ago. However, the Warburg hypothesis does not necessarily imply mitochondrial dysfunction. The alkyl-halogen, 3-bromopyruvate (3BP), would not be expected to have selective targets for cancer therapy due to its high potential reactivity toward many -SH side groups. Contrary to predictions, 3BP interferes with glycolysis and oxidative phosphorylation in cancer cells without side effects in normal tissues. The mitochondrial hexokinase II has been claimed as the main target. This "Organelle in focus" article presents a historical view of the use of 3BP in biochemistry and its effects on ATP-producing pathways of cancer cells. I will discuss how the alkylated enzymes contribute to the cooperative collapse of mitochondria and apoptosis. Perspectives for targeting 3BP to bioenergetics enzymes for cancer treatment will be considered.
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    • "The HK2 gene is up-regulated in cancer cells and is sometimes considered as the major gene responsible for Warburg’s glycolysis increase. Several glycolytic inhibitors that target HK2 have been proposed in cancer treatment [32], [33], [34]. PFKFB3 also plays a key role in glycolysis regulation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. "
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    • "CAF-secreted MMPs and other proteases also directly affect the motility and invasiveness of the cancer cells (Lochter et al., 1997; Boire et al., 2005) and help the cancer cells cross tissue boundaries and escape the primary tumor site (Stetler-Stevenson et al., 1993; Sternlicht et al., 1999; Boire et al., 2005). Aerobic glycolysis, which is also known as " Warburg effect " described the unique metabolic phenomenon that conversion of glucose into lactic acid is enhanced even in the presence of oxygen (Warburg 1956, Mathupala et al., 2009). Compared with normal somatic cells, tumor "
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