Over the years we have been characterizing mice with different Akt isoforms deficiencies for survival, lifespan, and susceptibility to cancer. The current renewal application is focused on new and unexpected observations made during the last funding period. These observations are: (i) Systemic whole body deletion of Akt1 in adult mice inhibits tumor progression in a mouse cancer model that is not driven by Akt activation. (ii) The deletion of either Akt1 or Akt2 does not inhibit liver carcinogenesis, and Akt2 deletion increases lung metastasis induced by liver carcinogenesis. (iii) The deletion of both Akt1 and Akt2 in the liver induces spontaneous hepatocellular carcinoma (HCC). (iv) Germ line deletion of Akt1 and Akt3 causes embryonic lethality, but the systemic deletion of Akt1 and Akt3 in adult mice is well tolerated. (v) The deletion of Akt1 increases the lifespan of mice. (iv) The systemic deletion of Akt1 and Akt2 in adult mice induces rapid mortality. These findings suggest that drugs, which target predominately Akt1 and not Akt2 could be effective and well tolerated in cancer therapy. By contrast, drugs that effectively inhibit both Akt1 and Akt2 could be deleterious and pro-liver carcinogenesis. Since Akt activation is perhaps the most frequently event occurring in human cancers, and targeting Akt activation for cancer therapy is in progress, our studies should have a profound impact on cancer therapy. The overall goal of this project is to determine the physiological consequences of Akt deletion in the mouse and their underlying mechanisms with implications to cancer therapy.

Public Health Relevance

Akt activation is perhaps the most frequently event occurring in human cancers, and targeting Akt activation for cancer therapy is in progress, our studies should have a profound impact on cancer therapy. Our findings suggest that drugs, which target predominately Akt1 and not Akt2 could be effective and well tolerated in cancer therapy. By contrast, drugs that effectively inhibit both Akt1 and Akt2 could be deleterious and pro-liver carcinogenesis. The overall goal of this project is to determine the physiological consequences of Akt deletion in the mouse and their underlying mechanisms with implications to cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG016927-16
Application #
8637580
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Finkelstein, David B
Project Start
1998-09-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
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

Showing the most recent 10 out of 47 publications