Mechanisms and Function of Autophagy in Cancer Summary The overall goal of this research proposal is to elucidate the molecular mechanisms of autophagy and its role in cancer. Autophagy is a lysosome-mediated, stress-responsive catabolic pathway that plays important role in both normal biology and disease. Although the core molecular pathway of autophagy has been relatively well delineated, how this pathway is precisely regulated to accomplish specific and sometime seemingly counterintuitive function is not clear. For example, what is the mechanism that enables ?autophagy-addicted? cancer cells to possess both intact mTOR activity and high levels of basal autophagy, considering mTOR is a bona fide inhibitor of autophagy? What is the role of autophagy in determining various cell fates such as cell death, senescence, and stemness, which are all relevant to tumorigenesis? What therapeutic implication can we learn from the answers to these basic biological questions concerning autophagy? In the previous funding cycle, we have observed potent anticancer effect of autophagy-inhibition in cellular and mouse models for multiple cancer types, including glioblastoma (GBM) and pancreatic ductal adenocarcinoma (PDAC). We discovered that a specific protein phosphatase 2A (PP2A) complex can be stimulated to enhance autophagy initiation through dephosphorylating the autophagy-initiating protein kinase complex, the ULK1 complex, thus counteracting the autophagy-suppressing activity of mTOR. Importantly, our preliminary results indicate that PP2A is also involved in the activation of TFEB transcriptional factor, a master regulator of autophagy gene expression and lysosomal biogenesis. Therefore, via regulating the ULK1 complex and TFEB, PP2A modulates both initiation and potency of autophagy. Intriguingly, we also found that autophagy and TFEB regulate GBM cell senescence under clinically relevant conditions. Based on these preliminary studies, in this grant, we will further investigate the molecular basis of autophagy and its role in cancer, by focusing on the following two aims: (1) the mechanisms by which protein phosphatases regulate TFEB, and the functional impact of such regulation on autophagy and autophagy-addicted cancer cells; and (2) the role of autophagy and TFEB in cancer cell senescence. To achieve these aims, we will conduct experiments that employ a combination of approaches, including standard cellular, molecular and biochemical approaches, animal modeling, and more specialized technologies such as quantitative mass spectrometry and deep sequencing. Success of the proposed study will lead to an in-depth mechanistic understanding of the regulation and function of autophagy in normal biology and cancer biology, and might provide insights into precise targeting of autophagy for cancer treatment. The proposal will also shed light on the functional interplay of autophagy with other important biological processes, including lysosomal biogenesis and senescence.

Public Health Relevance

The proposed study will lead to an in-depth mechanistic understanding of the regulation and function of autophagy in normal biology and cancer biology, and might provide insights into precise targeting of autophagy for cancer treatment. The proposal will also shed light on the functional interplay of autophagy with other important biological processes, including lysosomal biogenesis and senescence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166413-07
Application #
9831608
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2013-01-01
Project End
2023-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Wang, Weibin; Kang, Helen; Zhao, Yinu et al. (2017) Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib. J Clin Endocrinol Metab 102:634-643
Liu, Yuhui; Guardia-Laguarta, Cristina; Yin, Jiang et al. (2017) The Ubiquitination of PINK1 Is Restricted to Its Mature 52-kDa Form. Cell Rep 20:30-39
Puente, Cindy; Hendrickson, Ronald C; Jiang, Xuejun (2016) Nutrient-regulated Phosphorylation of ATG13 Inhibits Starvation-induced Autophagy. J Biol Chem 291:6026-35
Gammoh, Noor; Fraser, Jane; Puente, Cindy et al. (2016) Suppression of autophagy impedes glioblastoma development and induces senescence. Autophagy 12:1431-9
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
Kim, Sung Eun; Zhang, Li; Ma, Kai et al. (2016) Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol 11:977-985
Choi, Soyoung; Chen, Zhengming; Tang, Laura H et al. (2016) Bcl-xL promotes metastasis independent of its anti-apoptotic activity. Nat Commun 7:10384
Gao, Minghui; Monian, Prashant; Pan, Qiuhui et al. (2016) Ferroptosis is an autophagic cell death process. Cell Res 26:1021-32
Yun, Tao; Yu, Kaiwen; Yang, ShuangShuang et al. (2016) Acetylation of p53 Protein at Lysine 120 Up-regulates Apaf-1 Protein and Sensitizes the Mitochondrial Apoptotic Pathway. J Biol Chem 291:7386-95

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