Date of Award

2022

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Wade A. Russu

Abstract

Cyclin-dependent kinases (CDKs) and cyclins (Cyclins) are the core molecules in the regulation mechanism of the entire cell cycle. Cell cycle dysregulation is a common feature of human cancers, and inhibitors of cyclin-dependent kinases (CDKs) play a crucial role in cell cycle control and are one of the most promising areas of cancer therapy. We aspired to use our cyclin-dependent kinase 8 (CDK8) inhibitor, Q-12, as a probe for biomarker discovery for CDK8 inhibitor sensitive tumor types. Q-12 shows potent inhibition of cell viability and induction of apoptosis process in some triple-negative breast cancer (TNBC) and colorectal cancer cell lines in vitro. Western blot results indicate that Q-12 decrease p-STAT3 (Ser 727) stabilized p-STAT3 (Tyr 705) cause its upregulation. Cytokines are responsible for the increased phosphorylation of STAT3 (Tyr 705). Q-12 inhibit phosphorylation of CDK8 substrates STAT3 (Ser 727), STAT1 (Ser 727), E2F1 (Ser375) and reduce CDK8 protein levels. Q-12 initially increase E2F1 protein levels activated E2F1 and decrease Mcl-1 protein levels. All results suggest that STAT3 may not play a major role in cell death mechanism while E2F1 may play a major role. The main aim of the study is to investigate CDK8 inhibitor Q-12 effects on CDK8 and CDK8 substrates in triple negative breast cancer cell line MDA-MB-468, in order to better understand the mechanism of anti-proliferative effect of Q-12.

Pages

59

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