Thesis
Understanding O-GlcNAc transferase regulation of SIRT1 in breast cancer cells
Master of Science (M.S.), Drexel University
Apr 2016
DOI:
https://doi.org/10.17918/00010208
Abstract
Breast cancer is a deadly disease that is commonly diagnosed in women. There are many subtypes, including hormone dependent and hormone independent breast cancers. These various subtypes all eventually develop resistance to drug treatment. Thus, it is important to identify new therapeutic targets for breast cancer treatment. An area that holds promise is cancer metabolism. Cancer cells have an altered metabolic state known as the Warburg effect in which a majority of the consumed glucose is used for aerobic glycolysis even in the presence of oxygen. This process allows for cancer cells to produce the necessary material for biomass production. The enzyme O-GlcNAc transferase (OGT) has been shown to be elevated in breast cancers, resulting in increased O-GlcNAcylation. OGT is required for breast cancer cell growth and invasion. Our lab has recently shown that OGT regulates breast cancer cell invasion via the longevity protein SIRT1. Here, we identify the molecular pathway that OGT regulates SIRT1 in breast cancer cells. We show that the nutrient sensor 5' adenosine monophosphate-activated protein kinase (AMPK) plays a major role in SIRT1 regulation. Glucose deprivation, OGT inhibition and treating cells with AMPK activators induce expression of SIRT1 in breast cancer cells. In addition, we show that reducing levels of OGT in breast cancer cells leads to activation of AMPK. This activation is required for increasing levels and activity of SIRT1 as treatment with AMPK inhibitor blocked SIRT1 levels and activity in multiple breast cancer cells examined. In addition, using mouse embryonic cells containing AMPK knockout, we show that OGT regulation of SIRT1 requires AMPK. Taken together, our data suggests that OGT, and O-GlcNAcylation, controls levels and activity of SIRT1 in breast cancer cells through regulation of AMPK activity.
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Details
- Title
- Understanding O-GlcNAc transferase regulation of SIRT1 in breast cancer cells
- Creators
- Tong Lu
- Contributors
- Mauricio Reginato (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vi, 36 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- College of Medicine; Hematology and Oncology; Drexel University
- Other Identifier
- 991021889070804721