We found that in human prostate carcinoma and in lung carcinoma hexokinase 2 (HK2) expression is markedly elevated, while in normal prostate and lung cells its expression is hardly detectable. HK2 catalyzes the first committed step in glucose metabolism, and is highly expressed in glycolytic cancers. We found that ablation of HK2 in cancer cell lines significantly attenuate their tumorigenicity both in vitro and in vivo. In the first part of this proposal we wil employ mouse models of prostate carcinoma and lung carcinoma, which emulate human prostate and lung carcinomas. We will employ mice in which HK2 can be conditionally deleted in all mouse tissues. These mice will be crossed with mouse strains that develop either prostate carcinoma or lung carcinoma. Following tumor development, HK2 expression will be disrupted to determine whether HK2 deficiency per se can inhibit or reverse tumor progression without adverse physiological consequences. The proposed experiments would overcome a major obstacle that has historically precluded testing the feasibility of these approach, because germ line HK2 deletion is embryonic lethal in mice, but we can now conditionally delete HK2 in all adult tissues using HK2flox/flox mice. In the second part of this proposal, we will delineate the mechanism by which HK2 exerts its effect on tumor cells. We will employ both cancer cells derived from the mouse models and human cancer cells in these studies.

Public Health Relevance

Studies suggest that veterans are at a higher risk of developing prostate and lung cancer than the rest of the population. We found that in human prostate carcinoma and in lung carcinoma hexokinase 2 (HK2) expression is markedly elevated, while in normal prostate and lung cells its expression is hardly detectable. HK2 catalyzes the first committed step in glucose metabolism, and is highly expressed in glycolytic cancers. Our long-term goal is to develop strategies that selectively eradicate cancer cells by taking advantage of their accelerated glucose metabolism. We will test the feasibility of HK2 ablation for cancer therapy by silencing HK2 in human prostate and lung cancer cells in vitro and in vivo in mouse models of prostate and lung cancer. By employing a new mouse model where HK2 can be systemically deleted in all tissues we will test the feasibility that global ablation of HK2 could inhibit cancer progression without adverse physiological consequences. Because of cancer cells'addiction to glucose metabolism, this approach holds special promise for cancer therapy.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000733-03
Application #
8696773
Study Section
Oncology A (ONCA)
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Jesse Brown VA Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
DeWaal, Dannielle; Nogueira, Veronique; Terry, Alexander R et al. (2018) Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun 9:446
Petit, Lolita; Ma, Shan; Cipi, Joris et al. (2018) Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa. Cell Rep 23:2629-2642
Nogueira, Veronique; Patra, Krushna C; Hay, Nissim (2018) Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation. Elife 7:
Bone, Robert N; Evans-Molina, Carmella (2017) Combination Immunotherapy for Type 1 Diabetes. Curr Diab Rep 17:50
Wang, Qi; Yu, Wan-Ni; Chen, Xinyu et al. (2016) Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms. Cancer Cell 29:523-535
Hay, Nissim (2016) Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 16:635-49
Jeon, Sang-Min; Hay, Nissim (2015) The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch Pharm Res 38:346-57
Guzman, Grace; Chennuri, Rohini; Chan, Alexander et al. (2015) Evidence for heightened hexokinase II immunoexpression in hepatocyte dysplasia and hepatocellular carcinoma. Dig Dis Sci 60:420-6
Yu, Wan-Ni; Nogueira, Veronique; Sobhakumari, Arya et al. (2015) Systemic Akt1 Deletion after Tumor Onset in p53(-/-) Mice Increases Lifespan and Regresses Thymic Lymphoma Emulating p53 Restoration. Cell Rep 12:610-21
Patra, Krushna C; Hay, Nissim (2014) The pentose phosphate pathway and cancer. Trends Biochem Sci 39:347-54

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