Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. There is currently no cure for breast cancer and thus a greater understanding of the underlying biology of breast cancer will identify molecular targets and allow for the development of novel therapeutics. Cancer cells exhibit altered metabolism, characterized by increased glucose uptake and increased glycolysis under aerobic condition, a process known as Warburg effect. The exact molecular mechanisms underlying cancers dependency on metabolic pathways is unclear. Regulation of proteins by O- GlcNAcylation, post-translational modifications, is a reversible process that depends on glucose availability and is a powerful mechanism to regulate protein function. In this proposal, we will elucidate the mechanisms of how the nutrient sensor O-GlcNAc transferase (OGT), the enzyme responsible for catalyzing addition of O-GlcNAc to proteins, regulates cancer cell metabolism and survival stress signaling. Preliminary data suggests that O- GlcNAcylation regulates cancer metabolism via regulation of HIF-1? in a pVHL-dependent manner. Thus, we hypothesize that O-GlcNAcylation regulates cancer cell metabolism and survival stress signaling through VHL- dependent stabilization of HIF-1?.
In Aim #1, we will determine whether O-GlcNAcylation regulation of cancer cell survival requires ER stress and HIF-1? pathways.
In Aim #2 we will determine how alterations in O- GlcNAc regulate the tumor suppressor VHL protein and determine its contribution to O-GlcNAc-mediated regulation on cancer cell survival metabolism and survival in vitro and in vivo. These studies will further our understanding of how metabolic reprogramming in cancer cells connects at the molecular level to survival stress pathways and identify novel anticancer pathways.

Public Health Relevance

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. Approximately 50% of all patients with breast cancer become unresponsive to current therapies thus newer therapies must be identified to treat breast cancer patients. The proposed study will test whether targeting an enzyme (OGT) can alter nutrient pathways to induce stress and selectively kill cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA183574-01
Application #
8651577
Study Section
Special Emphasis Panel (ZRG1-F09B-P (20))
Program Officer
Bini, Alessandra M
Project Start
2013-09-17
Project End
2016-09-16
Budget Start
2013-09-17
Budget End
2014-09-16
Support Year
1
Fiscal Year
2013
Total Cost
$41,693
Indirect Cost
Name
Drexel University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ferrer, Christina M; Lynch, Thomas P; Sodi, Valerie L et al. (2014) O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell 54:820-31