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 altered metabolic pathways remains unclear. Our long-term goal is to elucidate how metabolic reprogramming in cancer cells regulates growth and survival pathways and to exploit these pathways for therapeutic gain. Regulation of proteins by O-GlcNAc 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), enzyme responsible for catalyzing addition of O-GlcNAc to proteins, regulates cancer growth and survival.
In Aim #1, we will determine how alterations in O-GlcNAc regulate the oncogenic transcription factor FoxM1.
This aim will elucidate the precise molecular mechanisms of how OGT targets FoxM1 for degradation via regulation of APC/C-Cdh1 and how this pathway effect growth control in cancer cells.
In Aim #2, we will investigate how OGT regulation of FoxM1 provides cell survival signals to cancer cells. We will determine whether alterations in O-GlcNAc causes FoxM1-dependent alterations of ROS levels leading to p53-dependent apoptosis of cancer cells. In addition, we will begin to identify apoptotic factors regulated by OGT/FoxM1 pathway.
The final aim will characterize and test whether novel OGT inhibitors can block cancer cell phenotypes in vitro and in vivo. These studies will further our understanding of how metabolic reprogramming in cancer cells connects at the molecular level to cell growth and survival pathways and identify novel anticancer agents.

Public Health Relevance

This grant will help elucidate molecular pathways altered in cancer. Specifically, we will focus on how metabolic reprogramming in breast cancer cells regulates growth and survival pathways. Additionally, we will test novel agents for their anti-tumor properties thus this proposal may help establish a new therapeutic target for treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155413-02
Application #
8236855
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Spalholz, Barbara A
Project Start
2011-03-04
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$322,051
Indirect Cost
$107,230
Name
Drexel University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sodi, V L; Bacigalupa, Z A; Ferrer, C M et al. (2018) Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation. Oncogene 37:924-934
Ferrer, C M; Lu, T Y; Bacigalupa, Z A et al. (2017) O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene 36:559-569
Ferrer, Christina M; Sodi, Valerie L; Reginato, Mauricio J (2016) O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling. J Mol Biol 428:3282-3294
Karakashev, Sergey V; Reginato, Mauricio J (2015) Progress toward overcoming hypoxia-induced resistance to solid tumor therapy. Cancer Manag Res 7:253-64
Sodi, Valerie L; Khaku, Sakina; Krutilina, Raisa et al. (2015) mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer. Mol Cancer Res 13:923-33
Kambach, D M; Sodi, V L; Lelkes, P I et al. (2014) ErbB2, FoxM1 and 14-3-3? prime breast cancer cells for invasion in response to ionizing radiation. Oncogene 33:589-98
Ferrer, Christina M; Reginato, Mauricio J (2014) Cancer metabolism: cross talk between signaling and O-GlcNAcylation. Methods Mol Biol 1176:73-88
Martín-Pérez, Rosa; Palacios, Carmen; Yerbes, Rosario et al. (2014) Activated ERBB2/HER2 licenses sensitivity to apoptosis upon endoplasmic reticulum stress through a PERK-dependent pathway. Cancer Res 74:1766-77
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
Ferrer, Christina M; Reginato, Mauricio J (2014) Sticking to sugars at the metastatic site: sialyltransferase ST6GalNAc2 acts as a breast cancer metastasis suppressor. Cancer Discov 4:275-7

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