Dr. Nissim Hay
- PhD, The Weizmann Institute, Rehovot, Israel
Mechanisms of cell survival, cell cycle control, metabolism, and genesis of cancer.
We are employing multiple approaches, including, cell biology, biochemistry, molecular biology and gene knockout, to study:
- the mechanisms by which certain oncoproteins and tumor suppressors regulate cell cycle, cell growth, and cell death; and
- the mechanisms by which growth factors promote cell survival.
During the past 15 years the major focus of this laboratory has been the role of the PI3K/Akt signaling pathway in the genesis of cancer and in cellular and organismal metabolism. The serine/threonine kinase Akt/PKB is perhaps the most frequently activated oncoprotein in human cancers. The hyperactivation of Akt in human cancers occurs largely through gain of function mutations in its upstream activator, the lipid kinase, PI3K, and through loss of function mutations in its upstream negative regulator the lipid phosphatase tumor suppressor PTEN that antagonizes PI3K.
This laboratory found that Akt is the major downstream effector of growth factor-mediated mammalian cell survival. Subsequently, this laboratory revealed that Akt activity is required for mitochondrial integrity, at least in part, through mitochondrial hexokinases, which catalyze the first committed step in glucose metabolism. Studies in this laboratory showed that Akt is sufficient and required for growth factor mediated activation of the mammalian target of rapamycin, mTORC1. In subsequent studies we showed that the role of Akt in energy metabolism is important for the full activation of mTORC1, and that mTORC1 is the principal downstream effector of Akt required for cell proliferation and susceptibility to oncogenic transformation. Based on these observations and observations made by other laboratories, pharmaceutical companies have been developing inhibitors of Akt for cancer therapy, and the of use rapamycin and its analogs for cancer therapy was initiated.
Over the years the laboratory has delineated the function of Akt at the cellular and organismal levels by targeting the Akt genes in the mouse. Single and compound Akt1, Akt2, and Akt3 knockout mice were characterized. Using Akt1 knockout mice, our laboratory provided a proof of concept that Akt activity could be reduced to a threshold level that inhibits cancer development in several mouse models of cancer, without eliciting severe physiological consequences.
Our laboratory provided evidence that the most evolutionarily conserved function of Akt in metabolism, particularly in energy metabolism, is coupled to its role in the genesis of cancer. More recently, we discovered the "Achilles' heel" of Akt. Akt activation in cancer cells increases the intracellular levels of reactive oxygen species (ROS), which are the byproducts of energy metabolism. While the elevation of intracellular ROS by Akt activation could potentiate tumorigenesis, it could also lead to the selective eradication of cancer cells displaying hyperactive Akt. Although Akt activation protects cancer cells from cell death induced by multiple stimuli, it does not protect from ROS-induced cell death. Thus, because Akt activation increases intracellular ROS, it sensitizes cells to killing by ROS. These observations prompted a therapeutic approach that selectively eradicates cancer cells displaying hyperactive Akt, while evading chemoresistance induced by Akt activation.
Ongoing projects in the laboratory include: further delineation of the roles of Akt in the genesis of cancer, metabolism, and lifespan; exploring new regulatory networks associated with Akt and its two most highly conserved downstream effectors, mTORC1 and FoxOs transcription factors; the role of mitochondrial hexokinase 2 in the genesis of cancer and implications for cancer therapy.
Jeon, S. M., Chandel, N. S., and Hay, N. (2012). AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661-665.
Nogueira, V., Sundararajan, D., Kwan, J. M., Peng, X. D., Sarvepalli, N., Sonenberg, N., and Hay, N. (2012). Akt-dependent Skp2 mRNA translation is required for exiting contact inhibition, oncogenesis, and adipogenesis. EMBO J 31, 1134-1146.
Segev, N., and Hay, N. (2012). Hijacking Leucyl-tRNA Synthetase for Amino Acid-Dependent Regulation of TORC1. Mol Cell 46, 4-6.
Chen, C.C., S.M. Jeon, P.T. Bhaskar, V. Nogueira, D. Sundararajan, I. Tonic, Y. Park, and N. Hay. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell, 2010. 18(4): p. 592-604.