Cdc25A is an instrumental protein phosphatase in cell cycle progression that is overexpressed in many types of human cancer. However, the role of Cdc25A in cancer metabolism is unclear, and although its role in the regulation of Cdk dephosphorylation is well established, Cdc25A may contain other important cellular substrates. We revealed that EGF stimulation induces PKM2 phosphorylation in the cytosol, which is essential for the nuclear translocation of PKM2. In the nucleus, PKM2 is dephosphorylated by interacting with Cdc25A, which is required for EGF-induced -catenin transactivation. We hypothesize that Cdc25A regulates cancer metabolism and tumor progression by dephosphorylating nuclear PKM2. To test this hypothesis, we will pursue three specific aims: (1) To further elucidate the mechanisms underlying Cdc25A-dependent PKM2 dephosphorylation and the subsequent activation of -catenin; (2) To determine the role of Cdc25A-dependent PKM2 dephosphorylation in the Warburg effect, tumor cell proliferation, and brain tumorigenesis; and (3) To determine the clinical significance of Cdc25A-dependent PKM2 dephosphorylation in human glioma. The proposed research is significant because it could lead to pharmaceutical approaches to interrupt cancer metabolism by blocking the function of Cdc25A; this would, in turn, improve the efficacy of human cancer treatment.

Public Health Relevance

Cdc25A is an instrumental protein phosphatase in cell cycle progression that is overexpressed in many types of human cancer. The goal of our proposed study is to elucidate the functions of Cdc25A in regulation of cancer metabolism during tumor development. This research is relevant to public health because it may help us identify molecular markers of prognosis and may lead to more effective cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS089754-02
Application #
9063150
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Fountain, Jane W
Project Start
2015-05-15
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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