During the last 20 years, we have been characterizing mice with different Akt isoforms deficiencies for survival, lifespan, and susceptibility to cancer at the cellular and organismal levels. The current renewal application is focused on the systemic effect of Akt isoforms deletion in adult mice. First, the systemic deletion of Akt1 and Akt2 as well as moderate to high doses of pan-Akt inhibitor in adult mice induces intestinal damage, loss of body weight, and eventually mortality. Thus, in the first part of this grant application we will delineate the mechanism of the intestinal damage and will employ approaches to alleviate it. Second, we found a marked discrepancy between the systemic effect and cell autonomous effect of Akt1 or Akt2 deletion on tumor initiation, progression, and metastasis. These results underscore the importance of determining the systemic effect of gene targeting for cancer therapy. We will delineate the mechanisms by which the systemic deletions of Akt1 or Akt2 in adult mice exert their effects on tumor progression and metastasis in mouse models of breast cancer.

Public Health Relevance

The PI3K/Akt signaling pathway is frequently hyperactivated in human cancers, and therefore is being targeted for cancer therapy. Pan-Akt inhibition or systemic deletion of both Akt1 and Akt2 induces adverse physiological consequences. Therefore, it is important to understand the cause of these adverse consequences in order to alleviate them and the contribution of the different Akt isoforms to the adverse consequences, and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG016927-23
Application #
10114179
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Fridell, Yih-Woei
Project Start
1998-09-01
Project End
2024-02-29
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
23
Fiscal Year
2021
Total Cost
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
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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
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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

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