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.
|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|
|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|
|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|
|Xu, P-Z; Chen, M-L; Jeon, S-M et al. (2012) The effect Akt2 deletion on tumor development in Pten(+/-) mice. Oncogene 31:518-26|
|Nogueira, Veronique; Sundararajan, Deepa; Kwan, Jennifer M et al. (2012) Akt-dependent Skp2 mRNA translation is required for exiting contact inhibition, oncogenesis, and adipogenesis. EMBO J 31:1134-46|
|O'Brien, Kelly A; Stojanovic-Terpo, Aleksandra; Hay, Nissim et al. (2011) An important role for Akt3 in platelet activation and thrombosis. Blood 118:4215-23|
|Park, Hyun Jung; Gusarova, Galina; Wang, Zebin et al. (2011) Deregulation of FoxM1b leads to tumour metastasis. EMBO Mol Med 3:21-34|
|Hay, Nissim (2011) Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta 1813:1965-70|
Showing the most recent 10 out of 30 publications