The PI 3-kinase/PTEN/Akt(PKB) signaling pathway has been recently emerged as one of the most frequently abrogated pathway in human cancer. Both PI 3-kinase and its downstream effector, the serine/threonine kinase Akt, posses oncogenic activity whereas PTEN that negates their activities is a tumor suppressor. PTEN is frequently inactivated by deletion or mutations in human cancer and heterozygous deletion of PTEN in mice induces diverse types of tumors. Thus far, the tumorigenic consequence of PTEN inactivation has been mostly attributed to elevation of Akt activity. Our long-term goal is to understand how does constitutive activation of Akt contribute to genesis of cancer at both cellular and organism levels. We have previously demonstrated that Akt promotes cell survival and blocks apoptosis induced by a variety of apoptotic stimuli and also induces protein synthesis. While these and other known activities of Akt may contribute to its oncogenic potential they may not be sufficient for Akt to exert its oncogenic function. In this proposal we intend to investigate a new activity of Akt as a regulator of DNA damage-induced G2/M checkpoint. We discovered this activity by showing that cells expressing activated Akt are resistant to exposure to 6-thioguanine (6-TG) and bypass the G2/M arrest induced by gamma-irradiation and 6-TO. This activity of Akt, which is independent of its anti-apoptotic activity and independent of p53, may be a critical determinant of its oncogenic function. We propose that the anti-apoptotic activity of Akt in conjunction with its ability to bypass G2/M checkpoint can lead to continuos cellular proliferation despite disruption of genome integrity. We will also determine the requirement of Akt for PTEN+/- induced tumorigenesis in mice by crossing PTEN+/- mice to Akt null mice. We have already disrupted the akt-1 gene in mice and crossed these mice with PTEN +/- mice to generate PTEN+/-/Aktl-/- mice. The requirement of Akt for the genesis of cancer in other mice models will be also determined. Finally, because of the frequent activation of Akt in prostate cancer we will focus on studying its role in prostate cancer by targeting activated Akt and dominant negative Akt to the mouse prostate. The studies presented in this proposal will have strong implications on determination of effective cancer therapy because many current therapy strategies rely on the induction of DNA mismatch repair, and G2/M checkpoint that lead to apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090764-02
Application #
6515005
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Freeman, Colette S
Project Start
2001-03-01
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$355,841
Indirect Cost
Name
University of Illinois at Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
121911077
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
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
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
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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