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.
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.
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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|
|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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