The serine/threonine kinase Akt is one of the most frequently activated protein kinases in human cancers, and therefore represents an attractive potential target for therapeutic intervention. However, it is not completely understood how activation of Akt contributes to the genesis of cancer, and whether it is feasible to ablate or reduce Akt activity in order to cure cancer. Our long-term goals are: 1) To determine why Akt is so frequently activated in human cancers. 2) To elucidate the mechanisms by which Akt promotes cell cycle progression and susceptibility to oncogenic transformation both at the cellular and organism levels. 3) To determine if it is feasible to partially ablate Akt activity to inhibit cancer development without any other severe physiological consequences. For this purpose we have generated mice deficient for the three Akt isoforms (Akt1-3) individually as well as compound mutant mice with all possible combined deletions. We are analyzing the phenotypes of these mice and examining their susceptibility to tumorigenesis. We will determine how much of Akt activity could be reduced to inhibit tumorigenesis, and could be tolerated without severe physiological consequences, and which Akt isoform is a better target for cancer therapy. Analysis of cells derived from these mice shows that Akt is required for normal cellular proliferation and susceptibility to oncogenic transformation. We are delineating the mechanisms by which Akt exerts its effect on cell cycle progression and susceptibility to oncogenic transformation. These studies will eventually determine the most critical downstream effectors of Akt required for these processes. The first part of this grant application will address the role of Akt in cell cycle progression, G2 cell cycle checkpoint, and oncogenic transformation at the cellular level. The second part of this grant application will address these issues at the organism level and assess the susceptibility of various Akt knockout (KO) mice to the development of various neoplasia. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090764-07
Application #
7226307
Study Section
Special Emphasis Panel (ZRG1-ONC-U (90))
Program Officer
Spalholz, Barbara A
Project Start
2001-03-01
Project End
2011-03-31
Budget Start
2007-05-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$364,986
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
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
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:
Liu, Shu-Lin; Wang, Zhi-Gang; Hu, Yusi et al. (2018) Quantitative Lipid Imaging Reveals a New Signaling Function of Phosphatidylinositol-3,4-Bisphophate: Isoform- and Site-Specific Activation of Akt. Mol Cell 71:1092-1104.e5
Hay, Nissim (2016) Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 16:635-49
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
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
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
Jayarama, Shankar; Li, Liang-Cheng; Ganesh, Lakshmy et al. (2014) MADD is a downstream target of PTEN in triggering apoptosis. J Cell Biochem 115:261-70

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