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Thesis
Targeting Cyclin-Dependent Kinase 5 (CDK5) in Glioblastoma
Master of Science (M.S.), Drexel University
Jul 2018
DOI:
https://doi.org/10.17918/h8mz-4m35
Abstract
Glioblastoma multiforme (GBM) is the most common brain cancer that develops from the malignant transformation of astrocytes and glial cells. The majority of their tumors occur due to dysregulation of cell cycle related-genes like cyclin-dependent kinases that promote uncontrollable cell proliferation and survival. Our lab has recently shown that O-linked N-acetylglucosamine transferase (OGT), an enzyme that catalyzes a O-GlcNAc posttranslational modification by adding a sugar moiety to proteins, is overexpressed in GBM. The addition of these sugar moieties can lead to the inappropriate stabilization of certain key proteins that can ultimately promote the survival of cancer cells. It is known that GBM preferentially utilizes acetate as an energy source synthesizing acetyl-CoA using ACSS2 (Acyl-CoA Synthetase Short Chain Family Member 2). Our lab has found that OGT regulates ACSS2 protein expression to fuel GBM growth by producing fatty acids and cholesterol. Our lab has also identified that CDK5 is responsible for phosphorylating ACSS2 at S267. We hypothesize that by targeting CDK5 either genetically or with a pharmaceutical inhibitor, we can block GBM growth and survival. Here we demonstrate that malignant human GBM cells lines are sensitive to the anti-proliferative ability of a pan-CDK dose-dependent inhibitor dinaciclib (SCH 727965) to inhibit anchorage-independent growth of GBM cells. Our results suggest that specific CDK-inhibitors that effectively and potently target CDK5 and its activity, specifically phosphorylation of ACSS2 (S267), is required for GBM growth. We postulate that pACSS2 (S267) may be a good biomarker for the monitoring the efficacy of CDK5-specific inhibitors. We have also found that knocking down CDK5 expression in GBM cells in vitro blocks oncogenic growth and induces cell death. Hence, we speculate that targeting CDKs and OGT may have important clinical implications in GBM formation, progression, and treatment.
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Details
- Title
- Targeting Cyclin-Dependent Kinase 5 (CDK5) in Glioblastoma
- Creators
- Rusia H. Lee - DU
- Contributors
- Mauricio Reginato (Advisor) - Drexel University (1970-)Todd Strochlic (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 53 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Medicine (Graduate); College of Medicine; Hematology and Oncology; Drexel University
- Other Identifier
- 8256; 991014632714504721