Thesis
Exploring cyclin-dependent kinase 5 (CDK5) as a novel therapeutic target in glioblastoma
Master of Science (M.S.), Drexel University
Jun 2020
DOI:
https://doi.org/10.17918/00001404
Abstract
Glioblastoma multiforme (GBM) is the most common and most aggressive form of primary malignant brain tumor. These tumors rely largely on acetate metabolism, facilitated by Acetyl-CoA Synthetase Short Chain Family Member 2 (ACSS2)-mediated conversion of acetate into acetyl-CoA. While the causes of GBM remain largely a mystery, cyclin dependent kinases (CDKs) have been recognized as critical mediators of tumor growth and progression. One such kinase, cyclin dependent kinase 5 (CDK5), is overexpressed in multiple cancers. Our lab has identified a pathway in GBM wherein overexpression of the enzyme O-linked N-acetylglucosamine transferase (OGT) facilitates CDK5-mediated phosphorylation of ACSS2 at Ser-267, inhibiting its proteasomal degradation. This enhanced stability of ACSS2 leads to increased production of acetyl-CoA, allowing for more rapid GBM cell growth. Here, we postulate that CDK5-mediated phosphorylation of ACSS2-Ser267 is critical for GBM growth, and therefore that targeting CDK5 may be a novel therapeutic strategy for treating GBM. Here we show that CDK5 levels and activity are elevated in GBM cell lines compared to normal brain cells, and elevated expression of CDK5 in GBM patients correlates with worse prognosis. We show that CDK5 loss reduces the proliferative capabilities of both established and primary GBM cells. Consistent with our model, loss of CDK5 function through both genetic and pharmacological methods reduces ACSS2-Ser267 phosphorylation in multiple GBM cell lines. Moreover, treatment of GBM cells with pan-CDK inhibitor Dinaciclib, which targets CDK5, also blocks clonogenic survival and neurosphere formation of cancer cells and demonstrates efficacy in a physiologically-relevant ex vivo model. Furthermore, growth-inhibitory effects of Dinaciclib can be reduced by expression of constitutive ACSS2-Ser267 phosphorylation mutant, illustrating the importance of this phosphorylation on GBM growth. Overall, our results suggest that specific and efficacious inhibition of CDK5 reduces GBM tumor growth in vitro and ex vivo. Therefore, we propose that CDK5 may be a viable novel therapeutic target in GBM.
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Details
- Title
- Exploring cyclin-dependent kinase 5 (CDK5) as a novel therapeutic target in glioblastoma
- Creators
- Rebecca A. Moeller
- Contributors
- Mauricio Reginato (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 66 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Medicine (Graduate); College of Medicine; Hematology and Oncology; Drexel University
- Other Identifier
- 991014695537304721