The serine/theronine kinase Akt, perhaps the most frequently activated oncoprotein in human cancers, and whose activation often exerts chemoresistance, is an attractive target for cancer therapy. Our long-term goals are to understand why Akt is frequently activated in human cancers, and to elucidate the mechanisms by which Akt activation contributes to the genesis of cancer, a critical step toward enhancing such therapy. We are using genetic approaches to evaluate the feasibility and the physiological consequences of Akt ablation for cancer therapy. Over the years, we have been delineating the functions of Akt both at the cellular and organismal levels. By employing mouse knockouts of the Akt genes, we uncovered several mechanisms by which Akt activity contributes to cell survival, cell proliferation, and susceptibility to oncogenic transformation. We employed several mouse models to show that Akt1 ablation inhibits the development of neoplasia in these models. The current major objectives of this grant application, at the cellular level, include understanding the role of Akt in cell proliferation and tumorigenesis and its dependence on mTORC1. At the organismal level, we will employ conditional deletions of the Akt genes in the mouse to determine the therapeutic effect on cancer developed in these mice. We will verify and further understand the consequences of Akt1 deletion versus Akt2 deletion on cancer development, progression and metastasis. Finally, we will assess whether the conditional deletion of hexokinase 2, a downstream effector of Akt, could affect tumor development, and whether it could be targeted for cancer therapy.

Public Health Relevance

The serine/theronine kinase Akt, perhaps the most frequently activated oncoprotein in human cancers, and whose activation often exerts chemoresistance, is an attractive target for cancer therapy. In order to target Akt activation in cancer, it is important to understand why it is frequently activated in cancer cells, and what are the critical downstream effectors of Akt. Our ultimate goal is identify the most critical downstream effectors of Akt required for the genesis of cancer, and to target them for cancer therapy. For these purpose we are employing both in vitro studies at the cellular level and in vivo studies at the organismal level.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090764-13
Application #
8448009
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
2001-03-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2013
Total Cost
$372,025
Indirect Cost
$131,894
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wang, Qi; Yu, Wan-Ni; Chen, Xinyu et al. (2016) Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms. Cancer Cell 29:523-35
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
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
Patra, Krushna C; Wang, Qi; Bhaskar, Prashanth T et al. (2013) Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 24:213-28
Halasi, Marianna; Wang, Ming; Chavan, Tanmay S et al. (2013) ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors. Biochem J 454:201-8
Stein, Jeffrey; Milewski, Wieslawa M; Dey, Arunangsu (2013) The negative cell cycle regulators, p27(Kip1), p18(Ink4c), and GSK-3, play critical role in maintaining quiescence of adult human pancreatic β-cells and restrict their ability to proliferate. Islets 5:156-69
Nogueira, Veronique; Hay, Nissim (2013) Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin Cancer Res 19:4309-14
Jeon, Sang-Min; Chandel, Navdeep S; Hay, Nissim (2012) AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485:661-5

Showing the most recent 10 out of 37 publications