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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166413-03
Application #
8777947
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
3
Fiscal Year
2015
Total Cost
$330,174
Indirect Cost
$143,424
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Puente, Cindy; Hendrickson, Ronald C; Jiang, Xuejun (2016) Nutrient-regulated Phosphorylation of ATG13 Inhibits Starvation-induced Autophagy. J Biol Chem 291:6026-35
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Monian, Prashant; Jiang, Xuejun (2016) The Cellular Apoptosis Susceptibility Protein (CAS) Promotes Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis and Cell Proliferation. J Biol Chem 291:2379-88
Yu, Xiaoliang; Li, Yun; Chen, Qin et al. (2016) Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1. J Virol 90:1088-95
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Gao, Minghui; Monian, Prashant; Pan, Qiuhui et al. (2016) Ferroptosis is an autophagic cell death process. Cell Res 26:1021-32
Wong, Pui-Mun; Feng, Yan; Wang, Junru et al. (2015) Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A. Nat Commun 6:8048
Gao, Minghui; Monian, Prashant; Jiang, Xuejun (2015) Metabolism and iron signaling in ferroptotic cell death. Oncotarget 6:35145-6

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