This research proposal seeks to investigate the molecular basis of autophagy and its role in cancer. Autophagy is a cellular catabolic process mediated by a unique intracellular membrane trafficking process and executed by lysosomal degrading activity. It is conserved in all eukaryotic cells and crucial for various physiological events. Deregulation of autophagy is a pathogenic factor for diseases including cancer, neurodegenerative disorders, infectious diseases and cardiac diseases. It has been established that a battery of autophagy-specific gene products form a central molecular pathway for autophagy. However, many questions still remain to be answered. For example, in mammalian cells, how does the central autophagy pathway sense various physiological and pathological triggers? What is the role of autophagy in cancer development and treatment, and is autophagy pathway a potential target for cancer therapy? Recently, we and others identified the ULK1-ATG13-FIP200 complex as an essential component of mammalian autophagy that mediates the activity of the nutrient-sensing kinase mTOR. Importantly, we found that upon amino acid starvation-induced autophagy, activation of the ULK1 complex requires both suppression of mTOR and stimulation of a specific protein phosphatase for ULK1. Further, we found that multiple therapeutic agents can stimulate autophagy in cultured glioblastoma cancer cells, and RNAi-mediated autophagy-blockage can potentiate the glioblastoma cell apoptosis induced by some of these therapeutic agents. These results underscore the clinical potential of autophagy-targeting in treatment of GBM, which is currently still a lethal disease with very limited therapeutic options. Built upon these preliminary studies, in this proposal, we will further study the mechanisms of autophagy and its relevance in cancer;we will also use mouse models for glioblastoma to investigate the potential role of autophagy in tumor initiation, maintenance, and treatment. To achieve these goals, we will employ a combination of approaches including molecular cellular biology, biochemistry, and animal modeling. This study will elucidate the molecular basis of mammalian autophagy and its potential therapeutic role in human cancer.
The long-term goal of this proposal is to understand the molecular mechanisms of autophagy, a conserved cellular process essential for normal physiology and involved in multiple human diseases, and to define the potential role of autophagy in development and treatment of the brain cancer glioblastoma. This study will elucidate the molecular basis of mammalian autophagy, and provide insights into development of novel therapeutic approaches to treat human cancer.
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|Gammoh, Noor; Florey, Oliver; Overholtzer, Michael et al. (2013) Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy. Nat Struct Mol Biol 20:144-9|
|Wong, Pui-Mun; Puente, Cindy; Ganley, Ian G et al. (2013) The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 9:124-37|