Thesis
Understanding the role of the OGT/CDK5/ACSS2 signaling axis on breast cancer brain metastatic growth
Master of Science (M.S.), Drexel University
Jul 2021
DOI:
https://doi.org/10.17918/00000821
Abstract
Breast cancer brain metastasis (BCBM) occur in almost 46% of triple negative breast cancer patients with a median survival of less than 5 months. Current efforts to treat BCBM are limited, and drugs used have proven effects on the primary tumors but lack specificity for the intracerebral tumor thus novel therapeutic targets are urgently needed. BCBM cells utilize acetate metabolism as an alternative fuel source to promote growth and survival via upregulation of Acetyl CoA Synthase 2 (ACSS2), the enzyme responsible for converting acetate into acetyl CoA. Previous work from our lab showed that primary brain cancers increase O-GlcNAc transferase (OGT) and O-GlcNAc levels and regulate acetate metabolism via phosphorylation of ACSS2 by the Cyclin Dependent Kinase 5 (CDK5). We have recently shown that OGT and O-GlcNAcylation levels are increased in BCBM cells compared to primary breast cancer cells and contain elevated levels of phosphorylated ACSS2. While the role of CDK5 is largely uncharacterized in cancer, elevated levels of CDK5 have been associated with poor prognosis in various cancers metastatic cancers including breast cancer. Here, we show that genetically targeting CDK5 in BCBM cells blocks ACSS2 phosphorylation and blocks breast cancer brain metastatic growth in vivo. Importantly, we show that pharmacologically targeting the OGT/CDK5/ACSS2 signaling axis in BCBM cells reduces tumor growth in vitro. Thus, the OGT/CDK5/ACSS2 signaling axis may represent a novel therapeutic target in treating breast cancer brain metastatic growth.
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Details
- Title
- Understanding the role of the OGT/CDK5/ACSS2 signaling axis on breast cancer brain metastatic growth
- Creators
- Emily Esquea
- Contributors
- Mauricio Reginato (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 37 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991015273171704721