The long-term objective of this proposal is to characterize and target those molecular events responsible for one of the most common, profound, and intriguing phenotypes of malignant tissues, i.e., their elevated capacity to utilize glucose, a critical carbon and energy source essential for cell growth. In earlier studies we identified hexokinase, the initial enzyme of glucose catabolism, as a major player and showed that, of its four major isozymes,only Type II is both highly overexpressed in tumors and bound to the mitochondria. Here, the enzyme is unregulated and produces the key metabolic precursor Glu-6-P at high rates. More recently while working at the gene level, we have made some very novel, definitive, and exciting progress, which for the first time in more than 6 decades, begins to shed light on the underlying cause of the highly glycolytic phenotype characteristic of numerous human cancers. Thus, we have shown that the Type II hexokinase gene is amplified, and upon isolating and characterizing its promoter in detail, demonstrated that it is activated, not only by glucose, insulin, glucagon, and cAMP, but also by both hypoxic conditions (common within highly malignant tumors), and by a mutant form of the tumor suppressor p53. These preliminary studies form a firm foundation for the studies proposed here which are focused on better understanding how the cancer- related Type II hexokinase gene is regulated, and how it can be successfully inhibited.
Specific aims are 4-fold and will be to: 1) Establish how the Type Il hexokinase gene, silent in many normal cells, e.g., hepatocytes, is """"""""switched on"""""""" during tumorigenesis; 2) Elucidate the molecular basis underlying the activation of the Type II hexokinase gene promoter by glucose; 3) Gain greater insight into the molecular basis and significance of the novel finding, that within tumor cells, the promoter for Type II hexokinase is activated by a mutant form of p53; and 4) Identify methods for arresting the growth of highly malignant cancers by selectively inhibiting the expression of the Type II hexokinase gene using antisense RNA and targeted gene disruption techniques. These studies are fundamental to our understanding at the gene level of one of the most common phenotypes of cancer cells, and are likely to lead to novel approaches for controlling the growth of highly malignant tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA080118-01
Application #
2744469
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Marks, Cheryl L
Project Start
1998-12-11
Project End
2003-11-30
Budget Start
1998-12-11
Budget End
1999-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mathupala, Saroj P; Ko, Young H; Pedersen, Peter L (2010) The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta 1797:1225-30
Pedersen, Peter L (2009) Mitochondrial matters of the heart: a plethora of regulatory modes to maintain function for a long lifetime. J Bioenerg Biomembr 41:95-8
Geschwind, Jean-Francois; Georgiades, Christos S; Ko, Young H et al. (2004) Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev Anticancer Ther 4:449-57
Ko, Young H; Smith, Barbara L; Wang, Yuchuan et al. (2004) Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun 324:269-75
Lee, Min Gyu; Pedersen, Peter L (2003) Glucose metabolism in cancer: importance of transcription factor-DNA interactions within a short segment of the proximal region og the type II hexokinase promoter. J Biol Chem 278:41047-58
Goel, Ashish; Mathupala, Saroj P; Pedersen, Peter L (2003) Glucose metabolism in cancer. Evidence that demethylation events play a role in activating type II hexokinase gene expression. J Biol Chem 278:15333-40
Pedersen, Peter L; Mathupala, Saroj; Rempel, Annette et al. (2002) Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta 1555:14-20
Geschwind, Jean-Francois H; Ko, Young H; Torbenson, Michael S et al. (2002) Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res 62:3909-13
Ko, Y H; Pedersen, P L; Geschwind, J F (2001) Glucose catabolism in the rabbit VX2 tumor model for liver cancer: characterization and targeting hexokinase. Cancer Lett 173:83-91
Mathupala, S P; Rempel, A; Pedersen, P L (2001) Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 276:43407-12

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