Mechanistic or mammalian target of rapamycin (mTOR) is a central controller of cell growth and proliferation in response to mitogenic and nutrient signals. mTOR pathway is frequently hyper-activated in human cancers, leading to uncontrolled cancer growth. Because cancer cells are often 'addicted' to elevated mTOR signaling, rendering mTOR a desirable cancer drug target. The highly specific mTOR inhibitors rapamycin analogs (rapalogs) are FDA-approved anti-cancer drugs for advanced renal and breast cancers. However, their efficacy is limited by lack of understanding of what patients are responsive to rapalog therapy. Therefore, a detailed understanding of mTOR signaling will is of considerable significance to basic biology and cancer therapy. In this application, we will investigate the mechanism of stimulation of cell growth and cancer by Rab1, a novel mTOR activator we recently identified. We will further study the role of Rab1 in the pathobiology and targeted therapy of breast cancer. We anticipate that successful completion of this project will help answer some long-standing questions on cell regulation and enable individualized cancer therapy.

Public Health Relevance

This project will investigate how cells modulate the growth engine in response to external stimuli. We will study a novel mechanism in this process, which should provide important new insights into long- standing questions in cell biology. Moreover, we will determine how dysfunction of this process can cause human breast cancer and influence the outcome of targeted breast cancer therapy. If successful, our research will help understand the underlying pathobiology and lead to new treatment of breast malignancies. It will also have implications for other types of cancer as well as diseases such as cardiac hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA173519-04
Application #
9059033
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Spalholz, Barbara A
Project Start
2013-08-14
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Rbhs -Cancer Institute of New Jersey
Department
Type
Organized Research Units
DUNS #
078728091
City
New Brunswick
State
NJ
Country
United States
Zip Code
Tsang, Chi Kwan; Chen, Miao; Cheng, Xin et al. (2018) SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation. Mol Cell 70:502-515.e8
Zhang, Shanshan; Li, Xiaoxing; Wang, Hui-Yun et al. (2018) Beyond regulation of pol III: Role of MAF1 in growth, metabolism, aging and cancer. Biochim Biophys Acta Gene Regul Mech 1861:338-343
Zhang, Hong; Li, Xiao-Xing; Yang, Yang et al. (2018) Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross-talk in hepatocellular carcinoma. Hepatology 67:2271-2286
Zhang, Yanjie; Huang, Bo; Wang, Hui-Yun et al. (2017) Emerging Role of MicroRNAs in mTOR Signaling. Cell Mol Life Sci 74:2613-2625
Che, Meixia; Wang, Ren; Li, Xiaoxing et al. (2016) Expanding roles of superoxide dismutases in cell regulation and cancer. Drug Discov Today 21:143-149
Wang, Ren; Ganesan, Shridar; Zheng, X F Steven (2016) Yin and yang of 4E-BP1 in cancer. Cell Cycle 15:1401-2
Li, Yue; Tsang, Chi Kwan; Wang, Suihai et al. (2016) MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription. Hepatology 63:1928-42
Yang, X-Z; Li, X-X; Zhang, Y-J et al. (2016) Rab1 in cell signaling, cancer and other diseases. Oncogene 35:5699-5704
Wang, Ren; Yin, Chen; Li, Xiao-Xing et al. (2016) Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner. Aging (Albany NY) 8:1184-200
Xu, Bi-Hong; Li, Xiao-Xing; Yang, Yang et al. (2015) Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A. Oncotarget 6:20813-28

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