This is the third competitive renewal of this grant application that was funded for the past 15 years. Over the years funding through this grant application led to several milestone observations and new discoveries, which include: The first description of Akt1-/- mice and the first genetic evidence that Akt is required for cell survival. Showing that Inhibition of early apoptotic events by Akt is dependent on the first committed step of glycolysis and mitochondrial hexokinase. The first phenotypic description of Akt1/2 DKO mice, and the first genetic proof that Akt is required for mTORC1 activation. Hexokinase- mitochondria interaction is required for Akt mediated cell survival. The first evidence that the deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. The first evidence that Akt1-/- mice are resistant to mammary gland and skin tumorigenesis, and that Akt exerts its pro-proliferative effect through mTORC1 activation. Finding the Achilles' heel of Akt, and that Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Finding that leptin deficiency is the underlying mechanism for Akt deficiency induced diabetes that can be cured by leptin administration. Employing for the first time sysytmic Akt1 deletion in adult mice to show that it could regress tumors after tumor onset. Systemic deletion of Akt1 and Akt2 in adult mice elicit rapid mortality and heaptic deletion of Akt1 and Akt2 surpsingly induces hepatocellular carcinoma (HCC). These recent findings manifest the importance of studying the function of the indvidual Akt isoforms not only in vitro in tissue culture, but also in a whole organsim epscially with respect to cancer therapy. In the first part of this renewal application we will follow mechansically our recent unexpected results. In the second part of this application, we will detremine the consequnces of deleting individuall Akt isoforms systemically and in a cell autonmous manner on breast cancer development and metastasis. Finally, we will exploit the role of Akt in metabolism to selectively eradicate cancer cells displaying hyperactive Akt in mouse models of prostate cancer.

Public Health Relevance

The serine/threonine kinase Akt, perhaps the most frequently activated oncoprotein in human cancers, and whose activation often exerts chemoresistance, is an attractive target for cancer therapy. However, there are three Akt isoforms, and it is not clear which one of them individually or in combination could be inhibited systemically for cancer therapy without severe adverse consequences. It is also important to identify alternative ways to selectively eradicate cancer cells displaying hyperactive Akt that do not require systemic inhibition of Akt. To address these questions we are not only employing in vitro studies at the cellular level but also in vivo studies at the organismal level using mouse models of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Xu, Wanping
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University of Illinois at Chicago
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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
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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
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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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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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