Our published and preliminary results, in the current funding period, support the idea that the role of Akt in energy metabolism is coupled to its role in the genesis of cancer. We have provided experimental evidence that the ability of Akt to inhibit apoptosis is dependent, at least in part, on mitochondrial hexokinases, which catalyze the first committed step in glycloysis and couple oxidative phosphorylation and glycolysis. Our results showed that the role of Akt in cell proliferation and susceptibility to oncogenic transformation is also coupled to its role in energy metabolism. We have shown that the most critical downstream effector of Akt, required for cell proliferation and susceptibility to oncogenic transformation is mTORC1. Akt activates mTORC1, at least in part, via the increase in intracellular ATP and the inactivation of AMPK, which otherwise inhibits mTORC1 activity. The ability of activated Akt to increase energy metabolism is also associated with accelerated ROS production. In addition, Akt inhibits ROS degeneration by inhibiting FoxO. The excessive accumulation of ROS mediated by Akt could certainly contribute to the genesis of cancer by increasing genetic instability. However, this is also the """"""""Achilles heel"""""""" of Akt since Akt cannot protect from ROS-induced apoptosis and thus in contrast to its ability to inhibit apoptosis in general, Akt sensitizes to killing by ROS. This provides a rationale for a strategy intended to selectively eradicate cancer cells with activated Akt and to evade Akt-induced resistance to chemotherapy. Intriguingly, our preliminary results showed that glucose and hexokinases, and in particular hexokinase II (HKII), can induce pro-oncogenic signaling pathways. We propose to delineate mechanistically this pro-oncogenic activity of HKII. Other preliminary results provided us with the opportunity to examine the roles of Akt isoforms and HKII in the development of HCC, and therefore the implications for HCC therapy. We will employ Akt1, and Akt2 KO mice as well as conditional HKII KO mice to address these issues.

Public Health Relevance

Studies in this grant application are intended to provide strategies for cancer therapy, and to evade chemoresistance induced by the most frequently activated pathway in human cancer. Studies are also intended to delineate the role of this pathway in the development of hepatocellular carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016927-13
Application #
8026859
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Finkelstein, David B
Project Start
1998-09-01
Project End
2014-01-31
Budget Start
2011-03-01
Budget End
2012-01-31
Support Year
13
Fiscal Year
2011
Total Cost
$397,906
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Yu, Pengchun; Wilhelm, Kerstin; Dubrac, Alexandre et al. (2017) FGF-dependent metabolic control of vascular development. Nature 545:224-228
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
Gao, Fei; Artham, Sandeep; Sabbineni, Harika et al. (2016) Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover. Cell Mol Life Sci 73:3917-33
Kerr, Bethany A; West, Xiaoxia Z; Kim, Young-Woong et al. (2016) Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium. Nat Commun 7:10960
Hay, Nissim (2016) Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 16:635-49
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
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
Li, Jing; Kim, Kyungho; Hahm, Eunsil et al. (2014) Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation. J Clin Invest 124:1483-96
Patra, Krushna C; Hay, Nissim (2014) The pentose phosphate pathway and cancer. Trends Biochem Sci 39:347-54

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